Abstract
Despite significant treatment efforts, pancreatic ductal adenocarcinoma (PDAC), the deadliest solid tumor, is still incurable in the preclinical stages due to multifacet stroma, dense desmoplasia, and immune regression. Additionally, tumor heterogeneity and metabolic changes are linked to low grade clinical translational outcomes, which has prompted the investigation of the mechanisms underlying chemoresistance and the creation of effective treatment approaches by selectively targeting genetic pathways. Since targeting upstream molecules in first-line oncogenic signaling pathways typically has little clinical impact, downstream signaling pathways have instead been targeted in both preclinical and clinical studies. In this review, we discuss how the complexity of various tumor microenvironment (TME) components and the oncogenic signaling pathways that they are connected to actively contribute to the development and spread of PDAC, as well as the ways that recent therapeutic approaches have been targeted to restore it. We also illustrate how many endogenous stimuli-responsive linker-based nanocarriers have recently been developed for the specific targeting of distinct oncogenes and their downstream signaling cascades as well as their ongoing clinical trials. We also discuss the present challenges, prospects, and difficulties in the development of first-line oncogene-targeting medicines for the treatment of pancreatic cancer patients.
Keywords: Pancreatic cancer, tumor microenvironment, signaling pathways, nanomedicine
Graphical Abstract
1. INTRODUCTION
The most aggressive, with a poor prognosis and subtle onset, pancreatic ductal adenocarcinoma (PDAC) has a high rate of mortality, with less than 10% of 5-year overall survival [1]. The American Cancer Society reports that while a 1–2% rise in five-year survival rates in the United States signals a potential turn in pancreatic cancer (PC) research, the scientific community is troubled by the uncertainty surrounding the possibility of a second leading cause of cancer-related death, with 49,830 Americans, in the coming year, 2030 [2]. For the last decade, surgical resection, followed by adjuvant chemotherapy, has stood as the most promising candidate for the treatment of PDAC. But the breath of patients with late diagnosis, metastasis state, and unrespectable condition is copped off gradually, even in the presence of systematic therapy. Since PDAC is surrounded by a dense tissue environment, such as complex desmoplasia. In contrast to other solid tumor microenvironments (TME), which prevents cytotoxic immune cell infiltration and the penetration of therapeutic agents by creating a stiff tissue barrier and leads to multidrug resistance and minimal therapeutic output.
Several research teams, including the European Study Group for Pancreatic Cancer-1 (ESPAC1), have demonstrated the major advantages of adjuvant chemotherapy versus resection techniques as part of clinical curative approaches. Two types of chemotherapeutics that are advisable and have been utilized to treat serious disease conditions are Folfirinox (folinic acid, fluorouracil, irinotecan and oxaliplatin) and gemcitabine (GEM) [3]. Although GEM remains the first choice for treating PDAC, its therapeutic effect remains poor due to the development of chemoresistance, rapid metabolism and insufficient delivery into the TME, which results in adverse effects on a healthy microenvironment. Another FDA-approved drug combination, including nanoparticle (albumin bound paclitaxel (Nab-Paclitaxel, commercially known as Abrexane) along with GEM, has demonstrated potential outcomes with a median survival of more than 8 months in advanced and metastatic PDAC patients [4]. Unlike the emergence of chemotherapy, which prevailed as a versatile outlook until now in the clinical phase, the narrow therapeutic index of radiation therapy remains a hurdle from a clinical point of view [5]. However, despite the success of tumor resection as well as combination adjuvant therapy, there is an urgent need for extensive studies regarding the complex cell biology of either the advanced or metastasis stages of PDAC in designing novel therapeutic strategies for it.
Targeted therapy is a clear option to balance the paucity of traditional chemotherapy. It targets the various biomarkers expressed in altered genomic mutations in the metastasis stages of PDAC disease. The major somatic target genes of interest, including KRAS, CDKN2A, TP53, SMAD4, BRACA1/2, and DNA repair, as well as the miRNA-linked signalling pathways (Scheme 1), are considered potential targets for the treatment of PDAC [6]. According to a report by Mahato’s team, miR-519C is down-regulated, and transfection of it into GEM-resistant pancreatic cancer cells causes a significant inhibition of Hypoxia-inducible factor 1 alpha (HIF-1) level under hypoxic conditions, attributing it as a novel therapeutic approach to prevent desmoplasia and hypoxia-mediated chemo-resistance in pancreatic cancer [7]. Cancer stromal cells exert too much pressure on angiogenesis, which leads to hypoxia, which changes the metabolic route of the tumor cells and produces invasiveness and chemoresistance in the TME. However, several efforts have been initiated in developing effective treatments for the delivery of therapeutic agents, but due to the lack of vascularization and presence of desmoplastic TME impede its efficiency.
Scheme 1.
Schematic representation of various signaling pathways related to the initiation and progression of pancreatic cancer.
Nanotechnology with intelligent techniques, including passive or active strategies, has been utilized to circumvent the challenge of reaching the drugs into the treatment-defiant status area of TME for the significant medication of cancers. Additionally, the PDAC hardly exhibits the increased enhanced permeability and retention (EPR) effect due to the presence of extensive desmoplasia. To selectively deliver therapeutic drugs to target cancer cells with the least amount of toxicity, various targeting molecules are decorated onto nanoparticles. Numerous nanovehicles, including liposomes, micelles, polymeric NPs, and metallic NPs, have been reported to be used as therapeutic platforms. However, the plasma stability and side effects of metallic NPs [8, 9] limit their clinical application. In this context, polymeric NPs and biodegradable lipids are suggested as promising delivery methods.
Our research team has been working diligently over the past few decades to develop novel redox-sensitive and cleavable polymeric NPs for non-targeted and receptor-mediated targeted delivery of therapeutic agents (Tables 1 and 2). We have also attempted to formulate lipid NPs, which are effective delivery vehicles for a variety of anticancer agents.
Table 1.
Summary of drug delivery using polymeric and lipid based nanocarrier
| Drug delivery system | Drug delivery mechanism | Delivery drug | Mechanism of drug actions | |
|---|---|---|---|---|
| mPEG-g-P(asp)-ss-GEM-g-DA | EGFR targeting, Glutathione responsive | Gemcitabine (GEM) miR-519c | Inhibition of HIF1α | |
| PEGB-PAEBEA | Passive targeting, ROS-responsive | Volasertib (BI6727), miR-34a | Inhibition of Polo-like kinase 1 (PLK1) | |
| mPEG-b-PCC-g-GEM-g-DC | Peptide GE11/HW12, pH-sensitive | GEM | Cell cycle arrest | |
| mPEG-g-PCC-g-CYP-gDC mPEG-g-PCC-g-DTX-g-DC | Passive targeting, pH-sensitive | CYP DTX |
Cell cycle arrest Hh inhibition | |
| C225-PEG-PCD)/mPEG-b-PCC-g-GEM-g-DC-g-TEPA | Cetuximab C225 monoclonal antibody, pH sensitive | GEM miRNA205 | Cell cycle arrest Chemosensitization Tumor suppression | |
| mPEG-b-PCC-g-DC | Passive targeting, pH sensitive | vismodegib (GDC-0449), Gemcitabine | Hh inhibitor, | |
| (mPEG-b-PCC-g-GEM-g-DC-g-CAT | Passive targeting, PH-sensitive | miRNA 205, Gemcitabine | chemosensitization | |
| PEGylated LA-GEM prodrug nanoassembly | a plectin-1 targeting peptide (PTP, amino acidsequence: H2N-KTLLPTPGGGC-COOH, pHsensitive | GEM | Arresting cells in the S phase | |
| GEM-lipid prodrug | Passive targeting, pH-sensitive | GEM | Arresting cells in the S phase | |
| Antibody fragmentinstalled polymeric micelles | Tissue factor (TF)-targeting Fab', Release is triggered by the ligand exchange of Pt(II) from the carboxylates in the block copolymer to chloride ions in the media, | Platinum (II) analog, dichloro(1,2-diaminocyclohexane) platinum (II) (DACHPt) | Its ability to form complexes with proteins and DNA in cancer cells, leading to their degradation and cell death | |
| Diblock copolymer poly(lactic acid)-azobenzene-poly(ethylene glycol) based polymersome | Passive targeting, Hypoxia mediated drug release | Gemcitabine and erlotinib | Cell cycle arrest, Blocking the epidermal growth factor receptor (EGFR) | |
| Radiation-cleavable antibody-and albumin-prodrug drug | EGFR targeting monoclonal antibody (aEGFRmAb), X-ray active drug release- | Doxorubicin or monomethyl auristatin E, MMAE | Inhibits cell division by blocking the polymerization of tubulin. | |
| Protease-sensitive linker Mc-Val-Cit-PABC-PNP | tumor targeted the anti-HER3 antibody 9F7-F11, Protease triggering drug release | monomethyl auristatin E, MMAE | Inhibits cell division by blocking the polymerization of tubulin | |
| Nucleoside modifiedionisable LNPs | Gene delivery by peritoneal macrophage exosome secretion | messenger RNA (mRNA) | protein expression occurred within insulin-producing β cells.. | |
| AV3, an ITGA5antagonistvia conjugation, loaded polydopamine (so called Apt-PDA@PTX/AV3) nanosphere | CD71-specific targeting aptamers, pH-sensitive release | Paclitaxel (PTX) | Inhibition of microtublin | |
| GEM prodrug-encapsulated amphiphilic dendrimer | Passive targeting, pH-sensitive drug release | GEM | Cell cycle arrest | |
| Dendrimer | Glutamyl Transpeptidase (GGT)-triggered and glutathione mediated drug release | camptothecin (CPT) | inhibit the nuclear enzyme DNA topoisomerase, type I, which is a key component in the process of DNA replication | |
| Exosome | Passive targeting, The RAB family proteins are thought to be involved in the binding of MVBs to the cell membrane, | CRISPR/Cas9 plasmid DNA | targeting the mutant KrasG12D oncogenic allele | |
| bBomimetic "Nutri-hijacker" with a "trojan horse, biguanide-modified albumin NPs | Passive targeting, Macropinocytosis, pH sensitive Drug release | Naringenin Biguanide | hijack and rewire metabolic addictions in KRAS-mutated (mtKRAS), Nutri-hijacker is a strong KRAS mutation-customized inhibitor | |
| Methoxy poly(ethylene glycol)-b-poly(carbonate-g-hexylamine) [mPEG-g-HX] selfassembly | Passive targeting, pHsensitive | GEM/SCH772984 code | GEM/SCH772984 code delivery for ERK inhibition. | |
| Self-assembling amphiphilic peptide nanoparticle (GENP) | EGFR targeting with GE11 peptide | GEM and poly(ADP-ribose) polymerase inhibitors (PARPi) olaparib | DNA damaging agents and PARP inhibitors | |
| Elastin mediated polymeric nanoassembly | LAEL peptide | Akt inhibitor | inhibited phosphorylation and consequent activation of Akt protein, blocked the NF-κB signaling pathway [ref: 112] | |
| Corosolic acid (CA)-entrapped long circulatory liposomes (LCLs) | endocytic CD163 targeting monoclonal antiCD163 antibodies (αCD163) | corosolic acid (CA)- | inhibiting STAT3 | |
| Cyclodextrin-grafted hyaluronic acid (HA-CD) and adamantine-conjugated heterodimers of pyropheophorbide a (PPa)-based NPs | Passive targeting | BRD4 inhibitor, JQ1 | immune evasion with the inhibition of c-Myc and PD-L1 expression, Inhibition of BRD4 | |
| Membrane-camouflaged PLGA nanoparticle | CPA/PTX drug | inhibitor of Hedgehog pathway | ||
| PEG-DB and PEG-PY systems | iRGD peptide, pH-sensitive | as gemcitabine (GEM) and a hedgehog inhibitor (GDC 0449), | hedgehog inhibitor | |
| pH-sensitive poly(amidoamine) clustered nanoparticles (LYiClustersiPD-LI) | Passive targeting, pH-sensitive | LY2157299 with siRNA | TGF-p receptor inhibitors (LY2157299) loaded with siRNA targeting PD-L1 (siPD-L1) | |
| HA-conjugated poly(styrene maleic acid) copolymer (HA-SMA) | anticancer agent 3,4-difluorobenzylidene curcumin-loaded | targeting of NF-κBsignaling pathways | ||
Table 2.
Summary of targeting of various signaling pathways using therapeutic agents and their clinical status.
| Serial number | Targeting signaling pathways | Targeting therapeutic agents | Mechanism of action | ClinicalTrials.gov identifier and Status |
|---|---|---|---|---|
| 1 | KRAS signaling pathways | R115777 | An oral farnesyl transferase inhibitor | Clinicaltrials.gov Identifier: NSC#70818, Southwest oncology group (SWOG 9924)/A phase II study' |
| 2 | KRAS signaling pathways | Selumetinib and MK-2206, modified FOLFOX (mFOLFOX) | Block the MEK and PI3K/AKT pathways downstream of the KRAS protein | Clinicaltrials.gov Identifier: NCT01658943. Phase 2 clinical trial, |
| 3 | KRAS signaling pathways | Small-molecule KRASG12D inhibitor, MRTX1133, | Block the mutated KRAS G12D protein | ClinicalTrials.gov ID: NCT05737706, A Phase 1/2 Multiple Expansion Cohort Trial |
| 4 | Mitogen-activated protein kinase kinase 1/2 (MEK1/2) pathway | Pimasertib plus gemcitabine | MEK1/2 inhibitor | ClinicalTrials.gov ID: NCT01016483, Phase I/II trial |
| 5 | Mitogen-activated protein kinase kinase 1/2 (MEK1/2) pathway | Trametinib (TRAM) | MEK inhibitor | Clinical trial identification: NCT02101788 A phase II/III trial, |
| 6 | RAF/MEK/ERK pathway | Sorafenib (BAY 439006, Nexavar) | Multikinase inhibitor, (EGFR-2 and VEGFR-3) and PDGFR-beta and Kit) | Clinical trial identification: NCT00079612, Phase I and phase II clinical trials, Phase III is ongoing |
| 7 | HER1/EGFR pathway | Gemcitabine plus erlotinib | Inhibit HER1/EGFR mediated signaling | Clinical phase II, ClinicalTrials.gov number, NCT01608841. A Phase III Trial, |
| 8 | VEGFR-1 targeting RTK pathways | Gemcitabine-erlotinib plus bevacizumab | Inhibition of VEGFR-1 | ClinicalTrials.gov number: NCT01214720 Phase III trial |
| 9 | VEGFR-1 targeting RTK pathways | Pazopanib, | an oral multikinase inhibitor | ClinicalTrials.gov NCT01099540. Phase II trial |
| 10 | PI3K, AKT, Rac (MAPK) | Ganitumab (a mAb antagonist of insulin-like growth factor 1 receptor) or conatumumab (a mAb agonist of human death receptor 5) combined with gemcitabine | Targeting of IGF and IGFR | A randomized, placebo-controlled phase 2 study |
| 11 | Phosphatidylinositol 3-kinase (PI3K) signaling pathways | Dinaciclib (SCH727965) and Akt inhibitor MK2206 | Blocking of Akt phosphorylation | ClinicalTrials.gov ID: NCT01783171 Randomized phase I trial |
| 12 | Hedgehog (Hh) pathway | IPI-926, a novel hedgehog pathway inhibitor, in combination with gemcitabine | Inhibition of Hh signaling | ClinicalTrials.gov Identifier: NCT01130142 Phase Ib/II trial. |
| 13 | WNT/β-catenin Ligand Signaling | Potent porcupine inhibitor ETC-1922159 | Inhibits Wnt signalling | ClinicalTrials.gov ID: NCT02521844 Phase 1A/B study |
| 14 | WNT Signaling | Ipafricept with nab-paclitaxel + gemcitabine | Blocks Wnt signaling | Clinical trial identification: NCT02050178 Phase Ib Study |
| 15 | TGF-β signaling | Galunisertib, a TGF-β inhibitor, NCT01220271 temozolomide | TGF-β signaling inhibition | ClinicalTrials.gov ID: NCT01220271 Phase 1b/2a study |
| 16 | Notch pathway | MK-0752, administered per weekly, in combination with gemcitabine | Inhibition by y-secretase inhibitors | ClinicalTrials.gov Identifier: NCT01098344 This phase I trial |
Additionally, most of the genomic targets are single pathways that result in insignificant outcomes, probably due to the dilution of targeting agents in the clinical phase [10]. An effective strategy focused on multiple genomic alterations at once with a combination of targeted agents is desired to achieve maximum efficiency against PDAC. As an extrinsic approach, molecular therapy approaches, including RNA interference (RNAi) therapy, small molecule inhibitors, immunotherapy, and antibodies, have recently been investigated to improve and lead to significant advancements in pancreatic cancer treatment. This strategy includes mediated targeting of signaling pathways at angiogenesis stages: epidermal growth factor receptor (EGFR), fibroblast growth factor receptor (FGFR), mitogen-activated ERK kinase (MEK), the phosphatidylinositol-3 kinase (PI3K), etc., but their clinical application remains uncertain.
In this review, we will outline the roles of numerous factors and conceivable processes that control the development of advanced pancreatic disorders. We will also discuss the current practice including findings of our research groups of targeting several active genes in nano-mediated pancreatic cancer therapies and how this may affect clinical applications in the future.
2. TUMOR MICROENVIRONMENT (TME)
The development of an environment that is frequently immunosuppressive, highly hypoxic, and low-vascularized, which results in tumor progression, chemoresistance, and metastasis is called the TME [Figure 1].
Figure 1.
Hallmarks of the pancreatic tumor microenvironment (TME), which consists of dense desmoplasia, stiff tumor tissue, and immunosuppressing cells under hypoxic condition. The stroma, a part of pancreatic ductal adenocarcinoma (PDAC) is programmed by paracrine and cell-cell interactions between cancer cells and cancer-associated fibroblasts (CAFs). These CAFs can be antigen-presenting, inflammatory or myofibroblastic, and can induce fibroblasts in the close proximity of cancer cells, promoting tumor growth. The functions of antigen-presenting cells (APCs) are controlled by dendritic cells (DCs) and tumor-associated macrophages (TAMs) as well as helper T cells (CD4+ T cells), promoting immunogenic antitumor activity against PDACs. However, several oncogene-mediated inhibitions of the immunogenic activities of TAMs, regulatory T cells (Treg), and myeloid-derived suppressor cells (MDSCs) build an immunosuppressive TME.
The TME is a very complex ecosystem in which numerous factors are involved. The prominent pathological characteristics of pancreatic cancer such as desmoplastic reaction, is characterized by an excessive proliferation of fibroblasts that are positive for alpha-smooth muscle actin (α-SMA) and by the deposition of different ECM components, which alter tissue heterogeneity, elasticity, and interstitial fluid pressure [11]. Poor microvascular density, observable leaky vasculature, a low perfusion level, and ensuing intratumoral hypoxia are complicated characteristics of desmoplasia in the pancreatic tumor setting. This reduced blood flow may be brought on by the fibrous stroma, and drug penetration into the tumor may be hampered by the stroma’s high interstitial pressure. Desmoplasia enhances the activity of anti-angiogenic factors, which can result in a hypoxic microenvironment. The aggressiveness of pancreatic cancer, including metabolic reprogramming, apoptotic suppression, prolonged proliferation, resistance, infiltration, and metastasis, depends on hypoxia, which is brought on by a lack of vasculature. Unlike other solid tumors, pancreatic cancer cells (PCs) have the ability to leak antiangiogenic substances into the hypovascular milieu, including angiostatin, endostatin, and pigment epithelium-derived substances. Additionally, ECM deposition can boost cancer cells production of endostatin, which further promotes hypoxia. The pathophysiology of PDAC is significantly influenced by interactions between the tumor and stromal ECM; nevertheless, further research is required to investigate the mechanism of the diseases.
Cancer cell proliferation necessitates metabolic demands that must be balanced with dietary intake. PDAC has particularly severe metabolic stress due to the hypovascular, fibrotic TME’s high hypoxia and scarce food supply [12]. Therefore, the growth and survival of PC depend on several acquired defects in nutrition intake and use, many of which are either directly or indirectly regulated by oncogenic KRAS. KRAS directs serum lipid and protein scavenging and improves the reception of external nutrients, including increased glucose uptake [13, 14]. Potential therapeutic targets are these modifications in cellular metabolism.
PC research has focused heavily on the relationship between anti-tumor immunity and the development of the disease. By removing cells with mutations and preventing them from developing into tumor cells, the immune system can inhibit tumor formation or progression during PC, whose progression may also be aided by immune suppression and metastasis. Clinical correlations between PC and tumor-infiltrating lymphocyte (TIL) population show that higher proportions of CD4+, CD8+, and dendritic cells (DCs) of TILs can improve the prognosis of affected individuals with PDAC [13]. A higher concentration of cancer cells adjacent cytotoxic T cells correlates with survival, and CD8+ T cells are essential for tumor cell killing among these immune cells. The activation of CD8+ T cells is suppressed, and the production of regulatory T cells (Tregs) is increased by PC cells, both of which contribute to immunosuppression. As a means of avoiding CD8+ T cell recognition, PC has been shown to decrease MHC I expression [16]. Therefore, the immunosuppressive process might be crucial for cancer cells to avoid immune system destruction, and it might also be a novel therapeutic objective for enhancing the effectiveness of immunotherapy.
2.1. Cancer-Associated Fibroblasts (CAFs)
Fibroblasts are cells primarily of mesenchymal ancestry and are present throughout the TME. They have several distinct roles, including regulating neighboring epithelial cells and proliferation, homeostasis, and the processes involve in wound healing. Fibroblasts are normally non-proliferating, which are developed into cancer-associated fibroblasts (CAFs) along with tumor cells in the presence of oncogenic pancreatic inflammation and malignant epithelial cells. This leads to the wound healing stimuli mediated oncogenesis [17].
Due to the microenvironment molds, CAFs exhibit a high degree of plasticity and regulate cancer metastasis and invasion through the ECM remodeling and synthesizing of various growth factors. They also play an important role on angiogenesis, tumor dynamics, medication accessibility, and therapeutic responses. In addition, CAFs receive signals from connected tissues that affect their function and expression profile. Therefore, the spatial location and origin of CAFs take an important role in phenotypic and significantly contribute to CAF heterogeneity. However, when pondering the origin of CAFs, the lack of clarity surrounding fibroblast-specific markers creates a problem [17]. It is challenging to put up theories regarding the source of CAFs because the markers of both tissue-resident fibroblasts and CAFs need to be better characterized. There is numerous evidence that CAFs contribute to the development of pancreatic cancer and treatment resistance. TME of PDAC is surrounded by severe desmoplasia which controls the CAFs to secrete various soluble components that cause treatment resistance. In addition, quiescent fibroblasts are activated by a variety of processes to develop activated phenotypes.
Growth factors that potentially encourage the recruitment and activation of CAFs include transforming growth factor beta 1 (TGF-β1), platelet-derived growth factor (PDGF), and fibroblast growth factor (FGF). TGF-β1 is secreted by the stromal cells and multiple lineages of leukocytes and stimulates the transformation of fibroblasts into myofibroblasts with the expression of α-SMA [18].
2.2. Desmoplasia
Significant fibrosis at primary tumor sites in pancreatic cancer, known as desmoplasia, is observed in PDAC pathological characteristics. Desmoplasia consists of ECM proteins, pancreatic stellate cells (PSCs), and immune cells. The role of PSCs in producing ECM proteins, cytokines, and growth factors that promote the proliferation of cancer cells present in the desmoplastic parts of PDAC. In addition, interactions of ECM proteins and desmoplastic-secreted growth factors with the pancreatic cancer cells activate intracellular signals, including reactive oxygen species (ROS) that promote chemoresistance to the cancer cells [16]. Therefore, desmoplasia of pancreatic cancer is a key factor in regulating the carcinogenesis of PDAC and responses to therapies.
The normal pancreas contains myofibroblast-like cells called PSCs, which have long cytoplasmic processes that wrap the base of the acinus much like pericytes to do for breast acini. PSCs comprise around 4% of the pancreatic cell population while dormant. The pathobiology of two major exocrine pancreas illnesses, chronic pancreatitis and pancreatic cancer, can also be discovered in the perivascular, periductal, and periacinar regions of the pancreas. PSCs engage in disease etiology in many illnesses after changing from a quiescent condition into an activated state known as myofibroblast [19].
The extensive desmoplastic activity surrounding the cancer cell glands in PDAC tumors makes them distinct and often more challenging to treat than other solid tumors. It is reported that provokes fibroblastic cell proliferation in PDAC usually results in poor prognosis. PDAC proliferation is influenced by desmoplasia, which comprises immune cells, myofibroblastic PSCs, and ECM proteins. The complex framework of desmoplasia offers the cancer cell growth and immune system with the stimulation of regulators and growth factors. Recent research has shown that the PSCs is the primary creator of ECM proteins and cytokines, chemokines, and growth factors throughout the development and progression of PDAC. However, the cancer cells of PDAC are capable of producing ECM proteins [19].
2.3. Hypoxia
Hypoxia is an important phenomenon in the development of PDAC and contributes significant role in the progression of angiogenesis, tumor survival and metastasis. Compared to normoxia, which corresponds to atmospheric oxygen pressure or 20% oxygenation in cell culture, hypoxia reflects a lower oxygenation level of less than 1.5%. It has been illustrated that most tumor tissues express a threshold of 2% oxygen 15 mmHg as physiological hypoxia, and 1% oxygen (8 mmHg) as pathological hypoxia that interfere with disturbs normal homeostasis. In this regards, pancreatic cancer is regarded as highly hypoxic, with low median oxygen level (less than 0.7%, 0–5.3 mmHg) compared to neighboring tissue, which has a median oxygen level of 1.2–12.3%. (9.3–92.7 mmHg) [20]. Pancreatic cells respond to hypoxia by activating transcription factors such as hypoxia-inducible factors (HIFs), which enhance the expression of associated genes involved in angiogenesis and glycolysis.
HIFs are heterodimeric transcription factors that are made up of an oxygen-regulated subunit and a constitutively expressed subunit (HIF1). HIF has three isoforms (HIF1, HIF2, and HIF3). HIF1/2 protein subunits are rapidly degraded by proteasomes in normoxia and have a short half-life (5 minutes). Under the hypoxic condition, HIF is stabilized and translocates into the nucleus, which binds to its target gene’s regulatory areas and regulates their transcription. HIF1 is a commonly used hypoxia marker [12].
The fast replication of cancer cells, desmoplastic fibrotic stroma, and poor vascularization, which elevate oxygen consumption and impair oxygen delivery, are the main causes of the hypoxic microenvironment of the PC. One of the independent PC prognostic variables is the existence of hypoxic patches inside the tumor, which is closely connected with tumor growth and with a worse prognosis than well-oxygenated tumors. More aggressive and treatment-resistant phenotypes are conferred by the adaptive response to hypoxia, which is predominantly mediated by HIFs in PC cells. When hypoxia is present, PC cells establish an effective adaptive metabolic response to meet the high demands for energy and biosynthesis. The metabolic switch from oxidative phosphorylation to glycolysis, when pyruvate is transformed into lactate instead of being oxidized through the tricarboxylic acid (TCA) cycle, is a significant intracellular adaptation to severe hypoxia. Pancreatic hypoxic cells have a higher glycolytic potential than aerobically metabolizing cells (the Warburg effect) [21]. This causes a stronger activation of all enzymes and transporters are involved in consuming glucose and producing lactic acid. Several studies have demonstrated that PC and stromal cells produce more reactive oxygen species (ROS) when hypoxia is present. Since oxidative stress and hypoxia are related, one of the most frequent regulatory responses to hypoxia is the generation of ROS. In PDAC cells, treatment with glutathione (GSH) inhibitors causes a marked rise in ROS levels and a brief upregulation of glycolysis. Hypoxia also contributes to the generation and activation of ROS in stromal cells, including PSCs, whose responsibilities are connected to their paracrine.
2.4. Immunosuppression
PC has a highly immunosuppressive TME that inhibits immunogenic activity, fosters cancer cell development, and facilitates local and distant metastasis. Traditionally, PDAC is a non-immunogenic neoplasm which may employ multiple means of immune evasion. To maintain the microenvironment, these components may produce extracellular chemicals such as matrix metalloproteinase, ECM, growth factors, and TGF-β. In general, the TME of PC is distinguished by an abundance of stroma, hypoxia, limited blood flow, and severe immunosuppression. According to research, the TME, which includes cancer-related fibroblasts, ECM, PSCs, various immune cells, and cytokines secreted by them, control PC cells proliferation, metastasis, chemoresistance, and immunotherapy [11].
2.5. Different cell types in tumor microenvironment (TME)
2.5.1. Pancreatic stellate cells (PSCs)
PSCs found at the base of pancreatic acinar cells and scattered around blood arteries, are critical cells in the microenvironment of pancreatic tumors. PSCs are resting under healthy conditions; however, in advanced stage of pancreatic cancer, altered PSCs can rapidly multiply and release a considerable amount of ECM and cytokines. TGF-β1, PDGF, Angiotensin II, and other cytokines. These cytokines bind to PSC receptors and activate several downstream signaling pathways such as ERK, c-Jun, p38, MAPK, and JAK-STAT, and stimulate PSC activation and proliferation [19]. Furthermore, active PSCs can release several growth factors via paracrine, thereby, activating EGFR, PI3K/AKT, and mTOR signalling pathways to promote PC cell proliferation. PSCs can also prevent PC cell death and improve their invasive ability. Additionally, PSC-induced vascular compression inhibits the delivery of therapeutic drugs to the TME, leading to GEM resistance.
2.5.2. CD4+CD25+Foxp3+ regulatory T cells (Tregs)
It is a well-established fact that PC is considered immunologically dormant. Tregs and cytotoxic T lymphocyte-associated protein 4 (CTLA-4) are prevalent in PC tissues. CTLA-4, which is consistently expressed on Tregs, plays an essential role in antigen presentation inhibition. In normal organisms, Tregs primarily induce immunological tolerance and serve an immunoregulatory role; however, it plays an immunosuppressive role in cancer patients. They facilitate immune escape by the suppression of effector killer cells. A low quantity of major histocompatibility complex-I (MHC-I) molecules in PC cells can prevent T cell activation, allowing CD8+ T cells to be activated by interacting with antigens communicated by MHC-I produced on antigen-presenting cells (APCs) [22]. CD8+ T cells that release perforin and granzymes and express Fas ligand can reduce the ability of anti-tumor cells. CD8+ T cells can also release immune checkpoint-related signaling components, affecting the activity of Tregs and causing immunological failure. Furthermore, Tregs can interact with APCs to limit the production of CD80 and CD86, causing cytotoxic T cells to malfunction.
2.5.3. Myeloid-derived suppressor cells (MDSCs)
Myeloid-derived suppressor cells (MDSCs), heterogeneous immature bone marrow cells, play an important role in PC immunosuppression. MDSC surface markers are typically CD11b+CD33+HLA-DR. Peripheral blood MDSCs and pro-MDSC cytokines are increased in PC patients [23]. Some research reports have suggested that peripheral blood MDSCs can be a sensitive measure of chemotherapy tolerance in PC patients. Furthermore, the granulocytic macrophage colony-stimulating factor (GM-CSF) can stimulate MDSCs in the bone marrow to multiply and move to the TME. GM-CSF is also linked to the transformation of bone marrow progenitor cells into MDSCs and recruiting MDSCs to the TME in PC. TME IL-10, IFN-γ, and TGF-β1 may activate MDSCs, promoting Treg proliferation and mediating immunosuppression [24]. Furthermore, MDSCs can produce reactive oxygen radicals, causing oxidative stress and encouraging carcinogenesis and growth of tumor cells.
2.5.4. Tumor-associated macrophages (TAMs)
In different circumstances, macrophages can differentiate into M1 and M2 phenotypes. M1 macrophages can stimulate local inflammatory responses and aid in immune surveillance. M2-type macrophages have been shown to increase tumor angiogenesis and cause chemoresistance, promoting PC proliferation, infiltration, and metastasis. IL-27, a histidine-enrich glycoprotein which can convert M2-type macrophages to M1-type macrophages and replicate its anticancer activity. TAM aids in the immunosuppression of PC cells as well as tumor-related angiogenesis. TAMs can be drawn to the TME by cytokines and vascular endothelial growth factor (VEGF). It promotes PC cell proliferation by secreting various growth factors [25]. IL-10, TGF-β1, and results in the development of an immunosuppressive TME by inhibiting the dendritic cell-mediated anti-tumor immune response. TAMs have also shown to block CD8+ tumor-infiltrating lymphocytes. Furthermore, studies have revealed that mast cells alter the development pattern of cancer cells by speeding up angiogenesis and boosting cancer cell motility.
2.6. Acidic extracellular pH
Most tumor cells, including PC, exhibit the metabolic adaptability of the “Warburg” effect [21]. Regardless of oxygen availability, tumor cells produce energy through glycolysis, which significantly increases glucose metabolism and produces a large amount of lactic acid. In addition, insufficient perfusion and chaotic vascular structure further increase the accumulation of lactic acid and hydrogen ions in the TME. Therefore, tumor ECM is acidic compared with normal tissue, with a pH range of 5.5 to 7.0. An acidic microenvironment induced PC by inhibiting tumor cell apoptosis and promoting cell proliferation, invasion, and immune escape.
2.7. High interstitial fluid pressure (IFP)
The structurally aberrant and permeable tumor blood vessels and lack of functioning lymphatic vessels elevate the interstitial fluid pressure (IFP) and approach microvascular pressure levels. Increased IFP is associated with increasing capillary hydraulic conductivity. Solid stress, capable of overcoming microvascular pressures, is mediated by ECM, specifically with hyaluronic acids. A decrease in IFP from the central regions to the tumor boundary leads to exudate tissue fluid movement in porous media. Increased IFP has been identified as one of the major obstacles to the uptake and distribution of therapeutic agents in solid tumors. AFs and desmoplasia can account for up to 90% of the tumor, leading to a high IFP that limits drug delivery to the tumor [26].
3. Therapeutic strategy
Treatment with surgical resection has been used for less than 20% of patients worldwide due to the complicated nature of the TME of PDAC and poor drug delivery to the tumor. Furthermore, a stiff ECM causes chemo-resistance as well as limited success with radiation therapy and makes it difficult to discover a cure. Although immunotherapy is being developed as an adjuvant therapy, immunosuppression is brought on by desmoplastic alterations in the ECM through the action of chemokines or receptor-mediated synergism. Therefore, the goal is now to target the impairment or eradication of CAFs and their related components prior to lymphocyte cell activation. Furthermore, recent preclinical research has promoted the use of active or passive targeting strategies mediated by NPs to treat frontline oncogenes and their downstream signaling networks.
3.1. Traditional chemotherapy
Prior to the revolution in cell-specific therapy, systematic therapy utilizing commercially available therapeutic drugs was regarded as a potent weapon against renegade of PDAC microenvironment. Studies utilizing human recombinant PH20 hyaluronidase (PEGPH20) to target desmoplasia enzymatically have improved drug delivery, vascular permeability, and therapeutic efficacy when paired with GEM [27], which is a pyrimidine nucleoside analog known for inducing S-phase arrest and inhibiting DNA synthesis. GEM is the first line FDA approved medicine for treatment of PDAC [28]. The benefits of using clinical translation have been demonstrated for 23.8% of GEM treatment compared to 4.8% for 5-fluorouracil (5-FU). The study has also exhibited modest survival advantages, with a median survival of 5.65 months compared to that of 5-FU (4.41 months), in diluting the complications related to detrimental PC. In a different clinical trial, GEM and Abrexane co-administration significantly has shown to improve overall survival (OS, 8.5 months) and median progression-free survival (PFS, 5.5 months) in a patient with metastatic PDAC compared to GEM alone (OS, 6.7 months, PFS, 3.7 months), which results in increased myelosuppression and peripheral neurophathy [29]. The first-line combination of nanoliposomal irinotecan (nal-IRI), oxaliplatin, 5-fluorouracil (5-FU), and leucovorin (LV) has been studied in the phase II/III research to determine its effectiveness in treating patients with advanced PDAC. Out of 56, 32 patients with controllable and tolerable side effects have received the maximum tolerated dose (MTD) of these treatments (nal-IRI = 50 mg/m2, oxaliplatin = 60 mg/m2, 5-FU = 2400 mg/m2, and LV = 400 mg/m2) every two weeks. Neutrophenia, fibrile neutropenia, and hypokalemia are the most frequent treatment-emergent adverse effects, with median PFS and OS of 9.2 and 12.6 months, respectively [30]. Similarly, NAPOLI-3 (NCT04083235), a randomized, open-label, phase 3 study with eligible patients having metastatic PDAC with NALIFIROX, has been applied on a two-week interval of a cycle of 28 days, as well as Abrexane (125 mg/m2) and GEM (1000 mg/m2) combination with the same time frame. The therapeutic efficacy has shown an improved median OS of 11.1 months for liposomal irinotecan plus 5-fluorouracil/leucovorin and oxaliplatin (NALIFIROX) compared to that of GEM and Abrexane combination with 9.2 months of median OS [31].
3.2. Advancement in therapeutic strategy
3.2.1. Targeted therapy
Although standard chemotherapy has shown a significant rate of patient survival across various clinical phases, recent studies into the genetic mutation in PDAC urge the need for targeted therapy. Poor treatment efficiency against PDAC is caused by the complex TME, which also has late symptom onset and innate genetic variants. It is yet to be determined how to analyze for relevant genetic pathways for targeted therapy.
Numerous PC cell lines have been the subject of in-depth research that revealed more than 60 gene modifications linked to 12 signaling pathways that may be affected by biomarker-directed targeted therapy and control both germline and somatic changes in the development of metastatic PDAC [31]. The map of gene mutations is mainly regulated by 5 oncogenes (>10%) of PDAC, such as Kirsten rat sarcoma (KRAS), TP53, CDKN2A, SMAD4, and CDKN2B (21%). These oncogenes mostly result in intracellular enzymatic phenomena, including MAP kinases, cell cycle, DNA homologous repair, PI3K-AKT signaling, chromatin remodeling, etc, [32].
3.2.1.2. Nanocarrier kinds and bonding strategies in prodrug
Targeted therapy, which may include monoclonal antibodies, small molecule inhibitors, etc., aims to block the specific cell surface receptors, signaling molecules, or active enzymes involved in cell migration and proliferation as well as the emergence of metastatic PDAC. By inhibiting such kinds of protein molecules with possible medications, neoplastic cell development is stopped and the signaling network is shut down.
Over the past ten years, numerous efforts have been made to alter the cellular and acellular microenvironments in an effort to increase the treatment efficacy in preclinical PC models and their translation into clinical trials with a minimum of systemic side effects [33]. Nanomedicine presents a promising approach to cross the stroma barrier and deliver therapeutic medicines into the TME by employing receptor-mediated active targeting mechanisms or passive targeting. The passive targeting relies on the enhanced permeability and retention (EPR) effect to effectively target the TME. However, a number of physiological barriers, the high level of stochasticity in the extravasation of tumor vasculature, as well as phagocytosis by macrophages, limit the amount of NPs accumulation in target tumor cells. Also, clinical trials face significant difficulties due to sophisticated production procedures and regulatory obstacles [34]. Active targeting, on the other hand, involves the delivery of therapeutic medicines by imbuing cell-specific ligands with NPs. This avoids non-specific binding to healthy tissues and minimizes systemic toxicity. Antibodies, proteins, peptides, vitamins, aptamers, and other ligands are known to interact specifically with overexpressed receptors on the TME, and their complexation facilitates both the internalization and endosomal transportation of cargo [35].
Lipid and polymer-based novel drug delivery systems (NDDS) enable large drug loading, improve plasma stability, and enhance therapeutic efficacy with minimal systemic toxicity. Their large surface area and self-assembly forms offer selective targeting to improve the drug’s pharmacokinetics, storage stability, systemic toxicity reduction, and drug disintegration prevention [36].
Different drug loaded polymeric micelles have been developed from the self-assembly of amphiphilic copolymers, including poly (lactic-co-glycolic acid) (PLGA), methoxy poly (ethylene glycol)-block-poly (2-methyl-2-carboxyl-propylene carbonate) (mPEG-g-PCD), methoxy poly (ethylene glycol)-block-poly(2-methyl-2-carboxyl-propylene carbonate-g-lactic acid) {mPEG-g-P (CB-g-LA)}. Their adaptable geometry and marginal sizes show promise in clinical translation for the potential delivery of anticancer agents into tumor tissues [37, 38]. PEGylation through coating or grafting with various polymers promotes extended blood circulation and gets beyond immune cell identification.
Drug molecules can either be physically cross-linked via interactions like hydrogen bonding, aromatic overlap, or chemically bound using stimuli-responsive linkers like thiol, amide or ester bonding (Figure 2B), depending on the structural characteristics of the polymeric cages. Stimuli-responsive linker mediated nanocarriers increase the stability of drug molecules in plasma and react to exogenous and endogenous factors including photo-irradiation, temperature, and intracellular variables, such as pH, glutathione and enzymes [Figure 2) [39].
Figure 2.
A) Synthesis of redox sensitive polyethylene glycol-g-P(Asp)-SS-GEM-DC prodrug micelles, B) Synthesis of enzyme sensitive (amide bond) polyethylene glycol-g-PCD-NH-GEM prodrug micelles, C) Synthesis of photo-cleavable drug-antibody prodrug micelles, D) Formulation of pH-sensitive and generic material loaded lipid nanoparticles (LNPs) In a simple and cost-effective approach, linoneic acid (LA) has been conjugated with GEM via amide bond linkage, followed by PEGylation and decoration with plectin-1 targeting. Protein-tyrosine phosphatase (PTP) peptide receptor is over-expressed pthe pancreatic cancer cells, leading to the formation of a self-assembly prodrug NPs.
The pH-sensitive linker such as hydrazone confers plasma stability of the prodrug at physiological pH 7.4 but undergoes degradation in an acidic environment (pH 4.5–6.5) in the tumor cells. On the other hand, endogenous enzymes like esterases and proteases/amidases, which are concentrated in the lysosome and tumor cells, target amide or ester-bonded prodrugs [40]. Particularly, lysosomal cathepsin B and matrix metalloproteinases (MMPs) actively attack amine acid sequence-based linkers such valine-citrulline sequences [41].
Following administration, the prodrug assembly has been demonstrated to internalize, and the amide bond is broken by overexpressed lysosomal cathepsin B to release GEM molecules. Particularly, lysosomal cathepsin B and matrix metalloproteinases (MMPs) actively attack amine acid sequence-based linkers such valine-citrulline sequences. These molecules then demonstrate superior anti-proliferative and apoptotic activities with 2.5 times lower IC50 values than free GEM against BXPC-3 cells and subcutaneous L3.6pl cancer cell-derived xenograft PDAC model [Figure 3] [42]. The amide-linked modification with mPEG-g-PCC block copolymer has also contributed to the extended stability and inhibition of deamination of GEM. The protease enzyme Cathepsin B therapy results in persistent GEM release (53.89% in vitro drug release) as well as strong anticancer action against NSG mice carrying MIA PaCa-2 cell-derived xenograft tumors [43]. Although amide bond-linked GEM-prodrug NPs have a potential effect in the treatment of PDAC, this type of bridging is unpredictable, and early plasma breakdown can lead to poor therapeutic efficacy and systemic toxicity.
Figure 3.
A) PDAC-homing peptide decorated lipid-based GEM prodrug to facilitate the endocytosis of nanoparticles and thereby augmented the cytotoxic activity against xenograft models of human PDAC. A) Schematic representation of the formulation of pectin-1 targeting peptide decorated GEM prodrug amphiphile nano-assembly into nanoparticles. In vivo therapeutic studies in a mouse model bearing L3.6pl cell-derived tumor xenografts, (B) Relative tumor growth versus time curves, (C) representative tumors on day 18, (D) body weight changes of the mice and (E) Ki-67 expression in immunohistochemistry. The mice were intravenously administered with saline, free GEM (7 mg/kg), nSNP, or tSNP (7 mg/kg GEM equivalent dose) via the tail vein. [Adapted with permission from “Wu et al., ACS Appl. Mater. Interfaces 2020, 12, 3327–3340”. Copyright (2020) American Chemical Society].
Since the 1960s, lipid nanoparticles (LNPs) have been utilized to deliver therapeutic molecules to cancer cells, consisting of cationic lipids, phospholipids, cholesterol, and PEGylation, for improving endosomal escape, stability, and blood circulation. The FDA has approved the use of liposome for the safe and effective delivery of cytotoxic drugs, including PEGylated liposomal doxorubicin (DOXIL®) [44]. Conjugation of small molecule drugs with cholesterol or fatty acid chains or lipid-prodrugs followed by incorporation into LNPs significantly enhanced d drug delivery to the tumor and their subsequent therapeutic efficacies (Figure 4) [45–50]. A comprehensive study by Coppens et al. on the conjugation of GEM with a collection of ascending lipid chains shows that the hydrophilic-lipophilic balance (HLB) in the lipid prodrugs is a crucial factor in the colloidal stability of the NPs as well as their cell toxicity. Despite having a larger loading capacity over the HLB threshold value of 8.49, this substance encourages the aggregation of lipid prodrug NPs. In this study, the squalene-GEM prodrug (size-90 nm), with its unique structural feature has been shown to exhibit considerable ‘in vitro’ cytotoxicity against cancer cells, indicating future preclinical benefit for the codelivery medicinal agents [51].
Figure 4:
Schematic representation of recently developed lipid-prodrug for the treatment of PDACDisulfide-linked drug-polymer conjugates stand out among them because of their propensity for reversible release in GSH-rich tumor cells (20 mM). Due to the hypoxic environment that promotes increased reactive oxygen species (ROS) production, tumor cells have hundreds of times more GSH than plasma (0.15 mM GSH) [Figure 2A]. As an illustration, Mahato’s research team recently published a study on the creation of epithelial growth factor receptor (EGFR) targeting peptide GE11 decorated and GSH-responsive disulfide-linked methoxy poly (ethylene glycol)-block-poly (aspartate-g-gemcitabine-g-dodecylamine) {mPEG-g-P(asp)-g-GEM-g-DC} for the treatment of PDAC [7]. The nanosystem shows considerable GEM loading (14%w/w) and accumulation of the micelles with 90% GSH mediated release of GEM to tumor cells while minimizing damage to normal tissues. Further, in vivo administration reveals suppression of HIF-1α with the significant reduction of orthotopic desmoplastic tumor in NSG mice. Similar to this, volasertib and miRNA have been shown to release quickly from ROS-responsive nanoassemblies constructed of poly (ethylene glycol)-poly[aspartamidoethyl(p-boronobenzyl) diethylammonium bromide (PEG-b-PAEBEA) and significantly inhibit tumor growth of PDAC [Figure 5] [52].
The creation of polymeric micelles with Fb-platinum loaded and one tissue factor (TF)-targeting Fab’ antibody decorated molecules has demonstrated to boost cellular binding and internalization by 15-fold, resulting in enhanced cytotoxicity (6-fold lower IC50 than non-targeted molecules) and the reduction of tumor growth in xenograft PDAC model [53].
Contrary to GSH and other factors, hypoxia-triggered medication release has also demonstrated exceptional value in the treatment of PDAC. BxPC3 cell-loaded hypoxia spheroid model indicates that under hypoxic conditions, more than 90% of the dye has been released through the rupture of polymersomes, which shows a significantly reduced level of cell viability [Figure 6] [54].
Figure 6.
Design of hypoxia-responsive linker based polymersome for the evaluation of in vitro toxicity against BxPC-3 cells. (A) Synthesis and systemic administration of Azobenzene incorporated hypoxia-responsive polymeric nanoassembly, (B) Comparison of viability of BxPC-3 cells in (B) monolayer and (C) spheroidal cultures against free drug, drug loaded PLLA5000-PEG2000 polymersomes (Control P), as compared to control (hypoxia-responsive polymersomes without any drugs), the hypoxia-responsive vesicles (Test P) under normoxic (black bars) and hypoxic (red bars) conditions (n = 6, * P < 0.05). [Adapted with permission from “Kulkarni et al., Biomacromolecules. 2016 August 08; 17(8): 2507–2513”. Copyright (2016) American Chemical Society].
Recently, photo-stimuli linkers have attracted a lot of focus in prodrug-mediated targeted cancer therapy. It offers possible cytotoxic drug release into the desired target cells as well as photonic energy dissipation through the production of ROS [55]. In an approach, a radiation-cleavable linker-based tripartite structure consisting of a radiation-responsive DMBA, monomethyl auristatin E (MMAE), and doxorubicin (DOX) prodrug has been created and subsequently modified with albumin and tumor targeted monoclonal antibody that has an affinity to binds EGFR (EGFR mAb)-expressed PDAC [56]. When exposed to X-rays, it encourages the release of more than 50% of the active medication under hypoxic condition, which increases cytotoxicity by a factor of 2000. The linker is eliminated, and the drug payload release is controlled by the production of hydroxylation radicals (Figure 2C). Similar research has been carried out by combining the protease-sensitive linker Mc-Val-Cit-PABC-PNP with the cytotoxic agent MMAE and tumor targeted the anti-HER3 antibody 9F7-F11. It has been demonstrated that MMAE-9F7-F11 ADC was internalized in BxPC-3 and HPAC pancreatic tumor cells and inhibited oncogenic survival through the cell cycle’s radiosensitive phase [57].
The pH-sensitive linker such as hydrazone confers plasma stability of the prodrug at physiological pH 7.4 but undergoes degradation in an acidic environment (pH 4.5–6.5) in cancer cells. In this regards, PEGlyated liposomes have been proven to be more successful in pH-sensitive complex formation, delivery and targeting of smacromolecules, such as plasmid DNA, miRNA or siRNA, for treating cancer cells.8]. The efficacy of LNPs has also been examined by the delivery of miR-634, which demonstrated the inhibition BxPC-3 cells generated tumor growth in mice [59]. Recently, Liu et al. have developed CD71-specific targeting aptamers decorated and dual inhibitors including microtublin inhibitor, PTX via noncovalent interaction and AV3, an ITGA5 antagonist via conjugation, loaded polydopamine (so called Apt-PDA@PTX/AV3) nanosphere, to target the PC cell environment. pH-sensitive release of therapeutic agents followed by near-infrared (NIR) irradiation exposure has shown to trigger the synergistic effect in impairing of desmoplastic TME as well as cooking of tumor cells in both ‘in vitro’ and ‘in vivo’ studies with the suppression of α-SMA and collagen-1 [60].
Contrary to LNPs or polymeric micelles, dendrimers, hyperbranched polymers with hydrophobic inner cores and outer ionizable sections, are known for their three-dimensional structure, allowing complex formation with generic materials and pH-sensitive delivery of nucleic acid in gene therapy applications. Using the film dispersion process, an aliphatic GEM prodrug-encapsulated amphiphilic dendrimer with less than 20 nm diameters has been created. The pH-sensitive prodrug dendrimer exhibits notable drug loading (33%) and encapsulation efficiency (69%). It promotes more than 80% control release under acidic TME conditions and displays exceptional antiproliferative activities against MIA PaCa-2 and SW1990 cell lines. The nanoassembly has also been demonstrated to be internalized at the tumor and to exhibit superior anticancer efficacy in pancreatic cancer SW1990 xenograft mice with the fewest side effects compared to free GEM [61]. Additionally, the formulation of prodrugs for camptothecin (CPT) that are glutamyl transpeptidase (GGT)-triggered and glutathione-modified PAMAM-conjugated helps the dendrimer promote excellent active targeting delivery of the medication [62]. With caveolae-mediated endocytosis, GGT converts the prodrug into its positively charged species, which is then absorbed in the deep tumor tissue and results in superior anticancer activity in patient-derived PDA xenografts and orthotopic PDA cell xenografts [Figure 7].
Figure 7.
Antitumor activity of pH-sensitive dendrimer-drug conjugates in mice inoculated with subcutaneous BxPC-3 cells or patient-derived exenograft (PDX) tumor cells. (A) Synthesis of dendrimer-camptothecin (GSHPTCPT) conjugate by loading camptothecin (CPT) to a PAMAM dendrimer via ROS-cleavable thioketal linker and surface modification with GGT-responsive GSH moieties. The cationization-initiated transcytosis of GSHPTCPT enabled the penetration of the nanosystem into the PDA tumor via bypassing the ECM. (B) Bioluminescence imaging and total luminescence intensity of all BxPC-3 cells generated tumor-bearing mice; (C) images of dissected tumors; and (D) the average tumor weight at the end of the treatment. [Adapted with permission from “Wang et al., ACS Nano 2020, 14, 4890–4904]. Copyright (2020) American Chemical Society.
Overall, with special characteristics such as a large surface-to-volume ratio, tuneable geometry, modifiable bioactive surface area, hydrophilic/hydrophobic ratio, and biodegradability, polymers are emerging as suitable nanodrug delivery systems (NDDS) to improve drug solubility and target PC. Despite the outstanding results of stimuli-responsive nanosystems in the treatment of PC, there is still a need to be met in the development of an efficient therapeutic system using the combination of NPs and chemotherapeutic agents in early-phase clinical studies.
3.2.1.3. Targeting Kirsten rat sarcoma viral oncogene homolog (KRAS oncogene)
Over 90% of pancreatic tumors in the G12 codon have the KRAS gene altered, making it the most frequent oncogene. It is a GTPase that controls the signal from the EGFR, fibroblast growth factor receptor 2 (FGFR2), and drives cell proliferation and growth by activating MAP kinases and PI3K/AKT signaling pathways. More than 30% of wild-type pancreatic tumors have MAP kinases enriched in KRAS [63]. Currently, KRAS inhibitors that are selective for KRAS mutations including G12D, G12S and G12R have been identified and several G12D-selective inhibitors are currently in clinical trials. However, direct inhibition of it is still challenging and remains as undruggable target.
3.2.1.3.1. Non-vector mediated inhibition of KRAS signalling pathways
The Phase II clinical [SWOG 9924] study on KRAS farnesyltransferase inhibition in the context of R115777 shows no therapeutic efficacy [64]. Targeting the associated protein-Ras downstream signaling pathways, such as MAPK and PI3K, may be a good approach for inhibiting cancer cell proliferation as inhibiting KRAS pathways typically raises important problems about its therapeutic application. The molecular inhibitors ARS-1620 and sotorasib have shown potential anticancer efficacy in a preclinical form of advanced PDAC illness harboring the KRASG12C mutation [65]. A potent ‘in vivo’ anti-proliferative impact against pan-cancer-1 has been seen with the specific KRAS inhibitors, Selumetinib and MK-2206. It has also been examined for the inhibition of MEK and Akt pathways in phase-II clinical studies, but their level of therapeutic impact is not as acceptable as that of modified FOLFOX (mFOLFOX) [66]. Recent approach to inhibit Gly-to-Asp mutated (KRASG12D) PDAC by the development of a small-molecule KRASG12D inhibitor, MRTX1133, has further opened a new paradigm in direct targeting of KRAS through immune modulation [67]. The potent MRTX1133 prompted the tumor cell apoptosis and remodelling of TME and its associated components including CAFs, complex desmoplasia, matrix, and macrophages. The ‘in vivo’ study also demonstrates that treatment of MRTX1133 has led to the rapid increase in intratumoral T cells and suppression of tumor growth in implantable and autochthonous PDAC model. Also, it plays a significant role in controlling the TME by enhancing M1-like macrophages as well as the loss of MDSCs, which include monocytic-MDSCs and granulocytic-MDSCs cells. Therefore, the investigation provides a rationale for the direct inhibition of KRAS oncogenes and its further translation into clinical testing [Table 1]. The discovery and identification of a noncovalent Pan-KRAS inhibitor (BI-2865) demonstrates the noncovalent interactions of common oncoproteins with particular mutant amino acids that inactivate them [68]. Three G-domain residues have put three distinct targets of KRAS under direct or indirect restrictions. It prevents the reactivation of KRAS-related downstream signaling, slows the development of cancer cells, and reduces tumor size in mice with KRAS G12C, G12D, G12V, and A146V mutant models without having a significant negative impact on animal weight. For the treatment of patients with KRAS-driven diseases, this discovery might be clinically significant.
3.2.1.3.2. Vector-mediated direct inhibition of KRAS signalling pathways
For the last few decades, advancements in nanotechnology have improved the targeted delivery of various small molecules, including gene therapy for the treatment of KRAS-mutated PDAC. CRISPR/Cas9 is a promising technology for gene editing-based targeting therapy. McAndrews has established the exosome mediated encapsulation of CRISPR/Cas9 plasmid DNA via transfection reagents for targeting the mutant KrasG12D oncogenic allele, which results in suppression of proliferation and inhibit tumor growth in orthotopic PC mouse models [69]. In another report, synthesized albumin NPs exhibited significant cellular uptake by cancer cells with an activating mutation of KRAS when compared to monomeric albumin [70]. Similar to this, Dou et al. have shown that albumin-bound prodrug of β-lap, nab-(pro-β-lap) NPs have increased absorption in KRAS mutant PDAC. With rising pharmacodynamic endpoints (e.g., PARP1 hyperactivation, γ-H2AX), it also demonstrates a considerable reduction of tumor development in KPC xenografts [71].
Recently, a biomimetic “Nutri-hijacker” with a “trojan horse” has been developed to hijack and rewire metabolic addictions in KRAS-mutated (mtKRAS) malignant cells to cause synthetic lethality. It has been demonstrated that the system made up of biguanide-modified albumin NPs interferes with glycolysis and aflavonoid synthesis, which lowers glutaminolysis and, in turn, reduces tumor fibrosis and immune regression in Nutri-hijacker internalized mtKRAS malignant cells [72]. The targeting of mtKRAS-driven metabolic processes in the PDAC model makes Nutri-hijacker a promising candidate for preventing KRAS signaling.
3.2.1.3.2.a. Inhibition of HIF1α signaling pathway
Biocompatible and hybrid LNPs with non-coding for siRNA against HIF1 and GEM as a chemotherapeutic agent have been developed to inhibit HIF1 signaling pathway for PC treatment in subcutaneous and orthotopic tumor models. PEGylated and cationic poly-lysine-co-polymer lipid bilayers (LENP) encourage the internal integration of GEM to the hydrophilic core and binding of negatively charged si-HIF1. Additionally, unique characteristics of LENPs regulate the prolonged release of GEM and stop siHIF1 from degrading in serum. In an orthotopic mouse model, LENPs show a synergistic impact in the reduction of tumor metastasis with the decrease of HIF1 [73]. An appealing therapeutic approach in tumor growth inhibition is the inhibition of KRAS downstream pathways, which includes the regulation of miRNAs.
Using a redox-sensitive mPEG-g-P(asp)-DA-based lipophilic copolymer, Xin et al. have demonstrated GEM transport and transfection of miR-519c into desmoplasia and hypoxic PC settings. GE11 decoration in the polymer that targets EGFR has demonstrated considerable accumulation in the TME and inhibited the growth of desmoplastic PC by downregulating HIF1α [7]. GE11 peptide (YHWYGYTPQNVI) ligand is well known for its specific interaction and binding to EGFR with low mitogenic activity. Using tumor-penetrating nanocomplexes (TPNs), Gillies et al. reported on the therapeutic delivery of anti-miR21 targeting oncogenic miRNAs, which are known to be connected with KRAS signaling pathways in PC development. TPN complex reveals a significant reduction in tumor volume and survival in patient-derived-organoid (PDO) avatars and PDX avatars [74]. More research has been done on siRNA delivery to KRAS-driven cancer cells using a peptide-based, oligonucleotide-condensing, endosomolytic NPs. By inhibiting KRAS expression, this causes NPs to accumulate in the tumor cells, which slows the tumor growth [75].
3.2.1.3.2.b. Inhibition of ERK/MEK/RAF MAPK pathways
Mitogen-activated protein kinases (MAPKs and extracellular signal-regulated kinases (ERK) are crucial signaling enzymes that phosphorylate adjacent proteins and control angiogenesis, cell proliferation, differentiation, and growth [76]. The activated ERK regulates a variety of substrates, including protein kinases, transcription factors, and cell death. Numerous MEK inhibitors, including pimasertib and trametinib, have been developed and put into clinical use over the past few decades; nevertheless, the interaction of signaling pathways and feedback activation has been employed to phosphorylate PI3K and mammalian target of rapamycin (mTOR), resulting in an unexpected failure of therapy [77, 78]. KRAS isoform specificity is necessary for targeting signaling and has been shown to be more potent against KRAS G12C mutations than G12D ones. Compared to MEK or ERK targeting alone, the combination of cobimetinib (a MEK inhibitor) and GDC-0994 (an ERK1/2 inhibitor) exhibits stronger anticancer effects both ‘in vitro’ and ‘in vivo’ [79]. However, the clinical stage falls short of the standards for further intervention, a different strategy with a low amount of toxicity is therefore necessary.
To target the ERK oncogene, new chitosan-coated solid lipid nanoparticles (c-SLN) co-loaded with ferulic acid (FA), an antioxidant, and aspirin (ASP) has shown a significant reduction in cell viability in human PC cells MIA PaCa-2 (45%) and Panc-1 (60%), respectively, demonstrating that it is capable of targeting the ERK oncogene. The immunohistochemical study of tumor tissue at post-therapeutic stages revealed a notable increase in the expression of the apoptotic proteins p-RB, p21, and p-ERK1/2 and a decrease in the expression of PCNA and MKI67 proteins, demonstrating the anticancer effectiveness of the combined therapeutic drugs [80]. Similar to this, Ray et al. have reported on a method for GEM/SCH772984 code delivery for ERK inhibition. The non-drug carrier made from methoxy poly(ethylene glycol)-b-poly(carbonate-g-hexylamine) [mPEG-g-HX] self-assembly copolymer exhibits loading capacities of GEM and SCH772984 (ERKi) of 20.2% and 18.3%, respectively, which is lower 50% growth inhibition (IC50) and increases GEM activities on PDAC cells [36]. In a different study, the therapeutic role of lawone-loaded PLGA NPs modified with folic acid (FA) and chitosan (CS) against Panc-1 cells has been thoroughly investigated. The NPs show that lawone encapsulation is greater than 80% and that cell growth is inhibited by 50% (IC50). Additionally, it shows considerable downregulation of BCL2 expression and upregulation of BAX gene expression, suggesting that it may activate apoptotic pathways to cure PC [81].
3.2.1.3.2.c. Receptor tyrosine kinases (RTKs) pathway
RTKs are a subclass of tyrosine kinases made up of many parts, such as an intracellular area, a single transmembrane helix, and an external ligand-binding domain. RTKs have the ability to regulate a variety of biological processes, including cell proliferation, spreading, and differentiation. Numerous studies on genomic biology have discussed the genomic changes of RTKs, including their subclasses as EGFR, HER2, MET, etc., and their essential significance in the development of metastatic cancer [82]. RTK activation is exclusively reliant on the tyrosine kinase domain’s association with the matching substrate, and it controls typical physiological processes including cell division and growth. When the substrates are expressed or secreted, RTKs become dysregulated, which causes harmful disorders like cancer.
Numerous efforts in using erlotinib, regorafenib as small inhibitors for the RTKS pathways in different cancer era but application in PDAC disease is still uncertain and unsatisfactory, probably due to the complex desmoplastic stroma (above 90%) in PDAC microenvironment [83].
A component of the RTK’s downstream signaling pathways is the platelet-derived growth factor receptor (PDGFR). PDGFR affects how cells are organized, including how the actin cytoskeleton is remodeled, how RAS-MAPK/Src is activated to control cell growth and proliferation, how PI3K/AKT and PLC are activated to cause cell migration, and more [82]. Additionally, PDGFR acts as a marker for CAFs, which have a substantial impact on the TME, lymphatic invasion, and lymph node metastasis of PDAC. As a result, the therapeutic approach focuses on the PDGFR-related differentiation of mesenchymal stem cells into those CAFs, which is thought to be a viable entry point for the treatment of PDAC.
A strong PDGFR inhibitor called Sunitinib has demonstrated superior therapeutic efficacy against the proliferation of vascular endothelial cells and enhanced progression-free survival when compared to the control group, but the majority of clinical trials indicate insignificant findings. Similar to GEM, sorafenib is a powerful RTKs inhibitor of PDGFR and serine/threonine-protein kinase B-raf (BRAF), and it has been used to treat patients with advanced PDAC, but the phase II/III therapeutic benefits are negligible [84]. Taken together by this study, it is explained by Goncalves et al. that RTKs are upregulated by various substrates and that only single-stage inhibition is not enough to inhibit the RTKs; a multi-step inhibition approach can thus be a suitable target to circumvent the drug resistance [85]. The active member of the ErbB family known as EGFR, which promotes the development, differentiation, survival of epithelial cells, and activates several signaling pathways, including the RAS-MAPK, PI3K/AKT/mTOR, and PLC-1-PKC. EGFR signaling regulates cancer metastasis via ECM-based mechanosensitization [86]. Like this, Sp1 promotes angiogenesis in the TME by activating Cyclooxygenase-2 (COX-2) via EGFR/p38-MAPK/Sp1 signaling via inclination specificity protein-1 (Sp1) [87]. It is anticipated that inhibiting EGFR signaling may be an effective therapeutic approach for the treatment of PDAC in its early stages. Overexpression of numerous oncogenic proteins can result from EGFR dysregulation caused by EGFR gene mutation, gene amplification, etc. According to a report in clinical phase II, with an average OS and PFS of 5.9–6.3 and 3.0–3.3, respectively, neither the monoclonal anti-EGFR antibody cetuximab nor the medication GEM demonstrate any substantial increase in the suppression of EGFR. The GEM plus erlotinib combination, in contrast to the cetuximab combination, has shown in rate of tumor growth inhibition., with substantial differences in PFS (median 5.9 vs. 2.4 months) and OS (median 8.7 vs. 6.0 months) when compared to erlotinib dose [88]. Erlotinib’s exceptional effectiveness in the suppression and treatment of PDAC with EGFR mutations has sparked interest in additional therapeutic use through the targeting of downstream signaling pathways.
As a part of nanocarrier-mediated targeting, Chitkara et al., have demonstrated that mPEG-b-P(CB-co-LA) copolymer has the potential capability to encapsulate and transport the hydrophobic drugs, cyclopamine (CPA) and gefitinib (GEF) into PC cells through EPR effect.
Multidrug carrier system reveals a synergistic effect against L3.6pl cells and an additive effect against MIA PaCa-2 cells in both ‘in vitro’ and ‘in vivo’ studies, assigning its potential impact on the activation of Caspase 3/7 activities for EGFR/Hh signaling mediated apoptotic cell death [38].
A study using GE11 peptide-decorated mPEG-g-PCC based micelle, displays EGFR-dependent higher cellular absorption and cytotoxicity (Figure 8). Modified nano-formulation also inhibits orthotopic pancreatic tumor growth more effectively than scrambled micelles and demonstrates substantial GEM release and accumulation in the microenvironment of the pancreatic tumor [89]. In a different study, EGFR-expressing human PC cell lines such BxPC-3, Panc-1, and MIA Paca-2 cells have been selected for using liposomes with curcumin and EGF grafts. Despite the fact that all cell lines have absorbed nanosystems, curcumin exhibits the greatest toxicity toward BxPC-3, indicating a unique and conceivable interaction with BxPC3 cell signaling [90].
Figure 8.
Evaluation of therapeutic efficacy of EGFR targeting GE11 peptide-modified PEG-g-PCD and mPEG-g-PCD-based mixed micelles against orthotopic pancreatic tumor models. (A) Formulation of GE11 peptide modified PEG-g-PCD and GEM grafted mPEG-g-PCD based mixed micelle for treatment of pancreatic cancer. B) In vivo efficacy of GE11-linked mixed micelles after systemic administration in orthotopic pancreatic tumor bearing mice, followed by a representative bioluminescence image from the mice treated with a saline, free GEM, HW12-linked mixed micelles, unmodified micelles, and GE11-linked mixed micelles (n = 5), (C) Relative photon intensity plot of all groups was measured from day 12 to day 30, [data represented as the mean ± SEM *p < 0.05; **p < 0.001 compared to GE11-linked mixed micelles], (D) Representative tumor sizes of each group were taken after sacrificing the mice at the end of the experiment, (E) tumor weight and (F) tumor volume were measured after sacrificing the mice at the end of the experiment. For all graphs, each data point represents the mean ± SEM (n = 5) *p < 0.001, **p <.0001, ***p < 0.05 (A) and *p < 0.001, **p < 0.05, ***p < 0.005 [Adapted with permission from “Mondal et la., Biomacromolecules 2016, 17, 301–313”. Copyright (2016) American Chemical Society].
In an orthotopic PDAC model, Singh et al. have shown how PEGylation enhances blood circulation and uptake into EGFR-targeted gelatin NPs. Redox-sensitive release of GEM-conjugated NPs exhibits significant anticancer efficacy compared to GEM therapy [91]. Similar investigations have also been explained with the thiolated PEG modified and EGFR targeted gelation NPs in terms of cellular uptake and the internalization of NPs into Panc-1 tumor xenograft models. EGFR targeted NPs have shown significant tumor targeting as compared to nontargeted NPs [92].
Further, the radio-labeled EGFR-targeted 131I–EGFR–BSA–PCL NPs have shown improved tumor accumulation and enhanced cytotoxicity in cancer cell killing than the non-targeted NP 131I–BSA–PCL [93]. The GE11 peptide-targeting engineered EGFR self-assembling amphiphilic peptide nanoparticle (GENP) has demonstrated a high level of GEM and poly(ADP-ribose) polymerase inhibitors (PARPi) co-delivery into tumor cells, leading to a significant suppression of tumor growth in a murine pPC mouse model with few side effects, attributing its suitability for the treatment of molecular defects in the DNA repair pathway [94].
Vascular Endothelial Growth Factor Receptor (VEGFR)
VEGFR expression in PC cells reveals tumor development as well as angiogenic and lymphangiogenic events. The growth and motility of PC cells are facilitated by the activation of the RTK receptors VEGFR-1 (also known as Flt-1), VEGFR-2 (also known as KDR), and VEGFR-3 (also known as Flt-4), which is mediated by VEGFR ligands [95]. A VEGF/VEGFR-targeted therapy has been developed for the treatment of PDAC, even though the TME of PDAC is associated with low microvascular density and hypoxia. Recent studies have shown the role of VEGFRs in tumor formation and the link between VEGF-A and a poor prognosis. In a study, Doi et al. have examined how anti-VEGF antibodies, bevacizumab, sunitinib, an RTK inhibitor that targets VEGFRs, and VEGFR2 siRNA affected PC cell’s ability to move. The outcomes show that phosphorylation of ERK (pERK) and AKt (pAKt) expression has decreased cell motility [96]. Despite the clinical phase III failure of the bevacizumab and GEM combination, including the treatment strategy for 535 patients with advanced PC, bevacizumab has shown potential efficacy for the treatment of multiple cancer cells. It is still being used in clinical trials against PDAC [97].
In a different report, Cutsem et al. describe a phase III trial against 301 patients with metastatic PC using a combination of bevacizumab (5 mg/kg every two weeks), GEM (1,000 mg/m2/week), erlotinib (100 mg/day), and/or GEM and erlotinib. The addition of bevacizumab does not show any further statistical improvement in OS or safety events, even though the PFS is longer with bevacizumab than with placebo [98]. Like this, pazopanib, an oral multi-kinase inhibitor, has been used to treat patients with metastatic gastroentero-pancreatic neuroendocrine tumors (NCT01099540) and has been shown to result in nine partial responses and a 75% drop-in control rate [99].
As a part of vector-mediated targeting, Spring et al. have demonstrated the function of cabozantinib (XL184, a multikinase inhibitor) loaded photoactivatable multi-inhibitor-loaded PLGA NPs for dual targeting, i.e., VEGF and MET (receptor tyrosine kinase for hepatocyte growth factor) signaling. Further, the size of XL184-loaded PLGA NPs has been engineered to be smaller in diameter than liposomes and encapsulated into lipid bilayer liposomes, so-called nanoliposomes (PMIL), which plays an important role in protecting the NPs from hydrolysis and systemic release of XL184. Upon photo-irradiation, the PMIL has been shown to promote the sustained release of drug molecules and a photothermal-mediated synergistic effect in killing tumor cells and damaging microvessels [100]. A similar kind of polymeric NP-mediated targeting of the vascular environment in PC has been reported by Leach et al. Anti-DLL4VNAR-encapsulated and maleimide-functionalized PLGA exhibits high binding affinity to DLL4-expressing pancreatic cancer cell lines and is endowed with an anti-angiogenic effect [101].
Insulin-like growth factor receptor (IGFR)
Insulin-like growth factor (IGF) expression that is out of control causes several signaling molecules, including PI3K, AKT, Rac (MAPK), and others, to become activated. These signaling molecules are linked to PDAC’s high rate of cell survival, growth, proliferation, transformation, and differentiation, as well as its metabolism of more than 70%. It causes pancreatic cells to metastasize with drug resistance in the TME [102]. Additionally, it has been shown that IGFR regulates blood glucose levels, pH, and oxygen levels, indicating IGFR has a key role in the development of a hypoxic environment in PD AC [103]. IGF1 secretion and IGF1R activation are tightly regulated by activated fibroblasts in advanced PC. As a result, there has recently been interest in creating sophisticated therapeutic approaches for the targeting of IGF and IGFR in preclinical and clinical phase trials. In 125 patients with metastatic PDAC, a phase II clinical trial has been conducted to evaluate the efficacy and safety of the mAb antagonists ganitumab (12 mg/kg every two weeks [Q2W]) and conatumumab (10 mg/kg Q2W) in conjunction with GEM (1000 mg/m2, days 1, 8, and 15 of each 28-day cycle) [104]. In ‘in vivo’ research, istiratumab with or without GEM has demonstrated positive feedback in the suppression of IGF1R and ErbB3 and blockage of PI3K/Akt/mTOR signaling pathways [105]. Awasthi et al. have shown the increasing therapeutic efficacy of Abrexane by the addition of an IGF-1R/IR inhibitor, BMS-754807, in AsPC-1 cell-mediated xenograft mice with PDAC models [106]. Prior to the ‘in vivo’ experiment, ‘In vitro’ data exhibits the decreasing IC50 dose of Abrexane in the presence of the IC25 dose of BMS-754807 and the increasing cleavage of caspase-3 and PARP-1 that enable the suppression of phospho-IGF-1R/IR and pAKT expression. Further, the ‘in vivo’ study reveals the significant reduction of tumor size for the combined treatment group, indicating the potential application of BMS-754807 in Abrexane toxicity in PDAC treatment.
Inhibition of Phosphatidylinositol 3-kinase (PI3K) signaling pathways
Mutant KRAS that works in conjunction with PDAC’s aggressiveness to promote tumorigenesis controls the active down-stream of PI3K. Additionally, KRAS activation makes it easier for PI3K to accept signals from numerous growth factor stimuli as well as cytokines via RTKs in cancer, which in turn helps to positively feedback on the oncogene’s action [107]. The PI3K signal also participates in the activation of mTOR, NF-kB, GSK3ß, p27, and Bad-Bax pathways to control cell growth, proliferation, motility, and metabolism as well. It is reported that targeting the PI3K/Akt/mTOR pathway has evidenced the improvement of survival in the genetic mouse model of PDAC [108]. In a review, Mehra et al. have demonstrated that the targeting of PI3K signaling pathways along with its downstream effectors, Akt and mTOR, with Urolithin A inhibitors reveals the ‘in vitro’ blocking of phosphorylation of Akt and p70S6K and improvement of survival in the genetically modified Ptf1aCre/+, LSL-KrasG12D/+, and Tgfbr2flox/flox (PKT) mouse model (GEMM) of PDAC as compared to vehicle control [109]. In another study, dose-dependent inhibition of pan-PI3K using Wortmannin and LY294002 has shown to induce apoptosis in PDAC with a decrease in tumor growth and metastasis in an orthotopic mouse model. The potential inhibitory effect is due to the blocking of Akt phosphorylation as well as increased terminal deoxynucleotidyl transferase-mediated apoptosis. A synergistic effect is observed while a suboptimal dose of LY294002 (25 mg/kg) in combination with GEM (62 mg/kg) is administered [110]. While the potent allosteric pan-Akt inhibitor MK2206 shows modest antitumor responses in patients with advanced PDAC stages, unbelievable and significant inhibitory effects of MK2206 are reported in combination with the cyclin-dependent kinase (CDK) inhibitor dinaciclib (MK-7965) in a preclinical mouse model of PDAC [111]. Therapeutic efficacy in targeting PI3K pathways mostly shows unsatisfactory results, probably due to the presence of resistance against PI3K inhibitors that is originated by the glucose-insulin feedback loop, thereby reactivating PI3K/mTOR signaling axis [112]. It has led to the dual targeting of PI3K and mTOR to prevent the re-activation of signaling pathways. To prone, Cao et al. have investigated the therapeutic effects of NVP-BEZ235 as dual-class inhibitors of PI3K/mTOR signaling in five early-passage primary PC-mediated xenograft mouse model, which results in the strongly suppressed phosphorylation of PKB/Akt and the inhibition of the ribosomal protein ser235/236 S6/Thr37/46 4E-BP1 [113].
Advancement of nanotechnology has led to the site-specific targeting of downstream signaling of KRAS including RTKs signaling. In this regards, Gonzalez-Valdivieso et al. have reported about the improvement of targeting of protein kinase Akt in PANC-1 and patient-derived PC cells (PDX models) through the formulation of elastin mediated polymeric nanoassembly decorated with a small peptide inhibitor of the protein kinase Akt. The nanoassembly with a size range of 73 ± 3.2 nm is found to be internalized into the cell body and suppress the phosphorylation and activation of the Akt protein and inhibit the activation of NF-kβ signaling pathway that further controls caspase 3-mediated apoptosis. Suitable delivery and prolonged blood circulation with minimal adverse toxicity in ‘in vivo’ experiments make it more versatile as an advanced therapeutic platform [114].
3.2.1.4. Inhibition of JAK/STAT Pathway
The Janus-associated kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathway promotes the growth of certain human malignancies, most notably PC. Trans-phosphorylation of JAK pathways results in the activation of JAK-STAT. JAK-related tyrosine phosphorylation and STAT translocation are encouraged by the activation of cytokine and growth factor receptors by interleukin-6 (IL-6) and EGF-ligand. The release of IL-6 ligand, VEGF, B-cell lymphoma-extra large (Bcl-xL) and MMPs also affects the inflammation, angiogenesis, apoptosis, invasiveness, and metastasis of PDAC [115]. The STAT3 signaling pathway is activated by IL-10 and TGF-β1, which reduces antitumor immunity and suppresses the immune system in the TME [116]. As STAT3 plays a crucial role in tumor formation, inhibiting STAT pathways may be a promising PDAC therapy option.
3.2.1.4.1. Nonvector targeting of JAK/STAT signaling pathways
JAK inhibition is used to stop STAT3 from activating laterally and to reduce the proliferation, invasion, and expansion of cells. The clinical uses of JAK inhibitors, such as tofacitinib, ruxolitinib, and pacritinib are primarily used for proliferative neoplasms and chronic inflammation, regardless of the type of solid tumor. Unsatisfactory results have been noted in the presence of capecitabine in a phase II clinical trial of ruxolitinib as a JAK1/2 inhibitor in 127 PDAC patients, despite higher expression of the inflammatory marker C-reactive protein (CRP) and a higher median OS for the treatment group compared to the placebo group [117]. Komar et al. have demonstrated the ‘in vivo’ treatment of ruxolitinib as a Jak1/2 inhibitor against metastatic PDAC that shows a significant reduction of STAT3 phosphorylation along with decreasing cell growth and differentiation and downtrend in the expression of the PSCs activation marker, α-SMA [118]. In a different study, JAK/STAT inhibition with AG490 is shown to suppress cerelein-derived COX-2, IL-1, and IL-6, which in turn suppresses STAT activation and contributes to the therapeutic benefits of STAT inhibition for pancreatic injury in severe acute pancreatitis (SAP) [119]. In addition, ruxolitinib has been shown to reduce the expression of various proangiogenic genes, including IL-22 and the IL-22 receptor (IL22R), thereby preventing the epithelial-to-mesenchymal transition (EMT) [120]. The scientific community is presently pushing phase I clinical trials for the FDA-approved JAK1/3 inhibitor tofacitinib, which has shown preclinical promise in treating prostate cancer (NCT04034238) [121].
In one study, the antimalarial medication chloroquine combined with GEM significantly inhibited CXCL12/CXCR4 signaling, which decreased phosphorylation of ERK and STAT3 signaling and improved overall survival in an in vivo model by effectively eliminating cancer cells [122]. Similarly, GEM and AZD1480, a JAK-selective small molecule inhibitor, together show a significant increase in tumor microvessel density with an increase ‘in vivo’ drug delivery and improved survival in both xenograft mouse models and PKT mice, without impairing collagen or hyaluronan layer with TME, suggesting their potential therapeutic benefit against PDAC [123].
3.2.1.4.2. Vector targeting of JAK/STAT signaling pathways
Mattheolabakis et al. have demonstrated the potential therapeutic effect of Phospho-valproic acid (P-V, a novel anticancer agent)-loaded PLLA-PEG NPs that exhibit significant suppression in STAT3 phosphorylation at the Ser727 and Tyr705 residues, where STAT3 plays a pivotal molecular target of P-V and extends an inhibition on acinar-to-ductal metaplasia in mice with activated Kras [124].
According to Anderson et al., there has been a notable result from inhibiting STAT3 specifically within human TAMs and targeting the endocytic CD163 scavenger receptor on TAMs using corosolic acid (CA)-entrapped long circulatory liposomes (LCLs) attached to monoclonal anti-CD163 antibodies (αCD163)—CA-LCL-αCD163. Additionally, CA-LCL-αCD163 has shown that reprogramming of M1 macrophages has increased the expression of pro-inflammatory cytokines, such as TNFα, IFNγ, IL-12, and IL-2, while suppressing IL-10 [125]. Wu and colleagues have reported on the antitumor efficaciousness of a liposome vehicle containing STAT3 inhibitor FLLL32 in a PANC-1 cells generated xenograft mice. The liposomes significantly inhibited cell proliferation in many pancreatic cancer cell lines when compared to FLLL32 alone. The induction of STAT3-associated target genes, including Bcl-xL, Survivin, and CCND1, has been demonstrated to be suppressed at a dose of 15 mg/kg Lip-FLLL32, suggesting that the drug is effective in both inducing apoptosis and promoting tumor growth. Additionally, radiation or Lip-FLLL32 alone, nanoformulation in conjunction with GEM and X-ray radiation has demonstrated superior tumor cell death [126].
3.2.1.5. Inhibition of hedgehog (Hh) signaling pathways
Hedgehog (Hh) pathways control crucial pancreatic development processes during embryogenesis in PDAC. The evolution of PDAC is caused by the diverted reactivation of Hh signaling in either canonical or non-canonical pathways [127]. The canonical route is governed by some selective receptors, including smoothened (SMO) receptor, patched (PATCH1/2) receptor, 7-domain receptor linked to G-protein coupled receptor (GPCR) as well as negative regulatory protein suppressor of fused homolog (SUFU) and glioma-associated oncogene homologs (GLI-1/2/3). Unlike the canonical route, non-canonical Sonic hedgehog (Shh) signaling includes PTCH-mediated, SMO-dependent, GLI-independent, and SMO-independent/GLI activation [128]. In this regard, PATCH1 suppresses activity and inhibits the translocation of the SMO protein of G-PCR into the primary cilium. The inactivated situation leads to the physical interaction between GLI and SUFU, followed by the desolation of GLI in the cytoplasm and restricting its movement to the nucleus. In active form, interaction of the Hh ligand with PATCH1 transmits the signal cascade to SMO to release GLI that is activated to translocate into the nucleus, thereby triggering transcription of the target genes through binding with their promoter [129]. The activated SHH causes the stroma to become more angiogenic by encouraging cell growth, angiogenesis, and metastasis. Blocking Hh signaling’s downstream activated pathways, such as PATCH, SMO, GLI, etc., can be an idealistic approach for treating PDAC because it plays a significant part in the development of metastatic PDAC. In this regard, the naturally occurring steroid alkaloid CPA has been identified as the first SMO inhibitor. CPA binds directly to the heptahelical bundle of SMO, preventing cell migration and prolonging survival by blocking the reactivation of Hh signaling pathways [130]. Similarly, the combined effect of CPA in the presence of GEM demonstrates the synergistic effect in inhibiting signaling pathways and reducing tumor growth in a xenograft mouse model [131]. While significant inhibition of Hh-dependent tumorigenes is observed in several cancer lines by using this drug, poor bioavailability and high toxicity restrict its application in clinical trials. The development of novel SMO inhibitors such as Vismodegib (GDC-0449), Sonidegib (NPV-LDE-225), Saridegib (IPI-926), BMS-833923, Glasdegib (PF-04449913), and Taladegib (LY2940680) has smoothed the field of PDAC treatment in respect of drug potency, pharmacokinetics, and tolerability as compared to cyclopamine [132]. In a phase II study, saidegib (patidegib IPI-926), a semi-synthetic derivative of CPA, in combination with GEM demonstrated mild improvement in patients’ responses with a PFS of 5.5 months as compared to placebo group [133]. Wang et al. most recently have looked into the SMO-inhibitory effects of NVP-LDE225 in patient-derived xenograft models with desmoplasia and therapeutic barrier features of PDAC. Cetuximab, a monoclonal antibody that targets EGFR, is distributed more widely inside the tumor as a result of its targeting, which also significantly slows tumor development compared to cetuximab only [134]. Despite the limited success of therapeutic approaches that target SMO signaling pathways, the majority of these trials encounter unsatisfactory results in solid tumors as a result of downstream oncogene events such as GLI activation, RAS/ERK, PI3K/AKT/mTOR-S6K1 signaling, p53 loss, and epigenetic changes. Therefore, it may be possible to increase the effectiveness and inhibitory effect of such medicinal drugs by potentially targeting GLI. It has been noted that GANT61, a GLi-antagonist, has a cytotoxic impact on PC lines. Similarly, the drug can also block CSC tumor growth through the genetic modulation that is responsible for cell growth, proliferation, and metastasis. Combination of this drug with an mTOR inhibitor reveals downregulation of EMT-associated different transcription factors such as Snail, Slug, and Zeb1 and the prevention of epithelial to mesenchymal transformation [135]. Unlike targeting GLI-DNA binding, the use of Arsenic trioxide (ATO) has demonstrated the substitution of zinc fingers and inactivation of GLi proteins [136]. In a xenograft PC model, its addition to GEM significantly reduces tumor growth and CSC markers. Compared to GEM, the clinical trial (NCT00053222) for PC patients has been boosted by the good impact of ATO in laboratory testing and has enrolled more patients.
3.2.1.5.1. Vector targeting of hedgehog (Hh) signaling pathways
Recent research has shown that the elevation of cell progression and chemoresistance in PDAC cells is highly correlated with the expression of BRD4, an epigenetic protein that activates the Shh signaling pathway. The chemotherapeutic drug GEM and targeting Bromodomain-containing protein 4 (BRD4) knockdown have a notable synergistic effect on cell apoptosis in PANC-1 and MIA PaCa-2 cells lines [137]. Similarly, Sun et al. have demonstrated the delivery of a photosensitizer and BRD4 inhibitor, JQ1, using cyclodextrin-grafted hyaluronic acid (HA-CD) and adamantine-conjugated heterodimers of pyropheophorbide a (PPa)-based NPs. PDT has played an important role in enhancing the immunogenicity of the tumor cells and intratumoral infiltration of the cytotoxic T-lymphocytes, while JQ1 has been shown to regulate immune evasion with the inhibition of c-Myc and PD-L1 expression [138].
Inhibition of downstream signaling, GLI-1, and EGFR expression of Hh signaling pathways has been investigated in MIA PaCa-2/L3.6pl cell lines by CPA and GEF-loaded polymeric micelles. Combination therapy shows significant upregulation of caspase 3 and 7 activity in GLI protein expression, which results in higher apoptosis in both cell lines as well as promising antitumor activity in L3.6pl-derived xenograft mice tumors [38]. In a different study, the restoration of miR-let7b and inhibition of Hh singaling using GDC-0449 through a methoxypegylated block copolymer exhibit synergistic effects in the suppression of cell growth, proliferation of different human PC cells (Capan-1, HPAF-II, T3M4, and MIA PaCa-2), and reduction of tumor growth in athymic nude mice bearing ectopic tumors alone [139]. Another combination comprising Hh signaling inhibitors, GDC-0449, and GEM shows effective inhibition of invasion, migration, and colony-forming features, as well as PARP cleavage and BAX-driven apoptosis of MIA PaCa-2 cells. Also, the ‘in vivo’ study demonstrates the decreasing of Hh ligands PTCH-1 and Gli-1 and EMT activator ZEB-1-related increased apoptosis and reduction of tumor growth in athymic nuclei mice [140]. Despite the potential role of GDC-o449 in blocking downstream Hh signaling, the emergence of resistance during GDC-0449 treatment is circumvented by the development of a novel analog, 2-chloro-N1-[4-chloro-3-(2-pyridinyl)phenyl]-N4, N4-bis (2-pyridinylmethyl)-1,4-benzenedicarboxamide (MDB5) that reveals a significant reduction of Gli-1 and Shh protein expression at transcriptional and translational levels, along with the suppression of ALDH1, CD44, and Oct-3/4, key markers of pancreatic CSC.
Further, MDB5-loaded NPs exhibit a significant decrease in tumor growth without a loss in body weight, indicating their potential application in PC treatment [141]. Similar synergistic inhibitory effects have also been observed in the growth and cell cycle arrest at M-phase of MIA PaCa-2 cells in the presence of CPA and microtubule stabilizer docetaxel (DTX) conjugated polymeric micelles [142]. The CPA-LLP system for targeted irradiation against MIA PaCa-2 human PC has been described by You et al. When used with MIA PaCa-2 cells generated xenografts in mice, the combination treatment shows anticancer activity and increases mouse survival models [143]. The synergistic effect of PTX and CPA in polymer micelle formulation (M-CPA/PTX) also showed a noteworthy decrease in stroma-producing CAFs and a suppression of tumor cell survival through micro-vessel density modulation, hypoxia mitigation, and matrix stiffness reduction without interfering with ECM network function [144]. A similar type of impairment with the enhancement of tumor perfusion in TME of PDA has also been demonstrated by a biocompatible and size-controlled erythrocyte membrane-camouflaged PLGA nanoparticle-stabilized CPA/PTX drug combination. This has led to the significant transport of PTX molecules and inhibition of tumor growth in vivo model, indicating their potential therapeutic effect in the clinical phase [145]. A study by Ray et al. have shown that PEG-DB and PEG-PY systems, which are decorated with iRGD peptide and pH-sensitive N, N’-dibutylethylenediamine/2-pyrrolidin-1-yl-ethyl-amine side chains conjugated PEG-PCC block colpolymer, allow for the significant delivery of therapeutic agents, such as gemcitabine (GEM) and a hedgehog inhibitor (GDC 0449), at endosomal pH in the intracellular environment, thereby suppressing pancreatic cancers [146]. An antimalaria drug, anthothecol, a natural product encapsulated in PLGA nanoparticles (Antho-NPs), has shown remarkable effects in suppressing cells, spreading, pluripotency-maintaining factors, and upregulation of E-cadherin, as well as killing of self-renewable pancreatic CSCs, isolated from human and Kras (G12D) mice. Additionally, the NP has a prominent effect on disrupting the binding of Gli to DNA and inhibiting Gli transcription and Gli target genes [147]. Similarly, mangostin-encapsulated PLGA nanoparticles (Mang-NPs) have been shown to exhibit comparable forms of growth suppression of pancreatic CSC ‘in vitro’, in humans, as well as in KC mice (PdxCre; LSL-KrasG12D) mouse models. Inhibitory effects of Mang-NPs have also been observed for N-cadherin, c-Myc, transcriptional factors Nanog, Oct-4, and components of SHH signaling pathways [148]. Through the formulation of polymeric nanocapsules, Ingallina et al. have demonstrated the exceptional percentage loading (~90%) and distribution of Glabrescione B, the first chemical that binds the hedgehog (Hh) modulator Gli1 into the tumor environment. As part of a multimodal therapy plan, the nanocapsules exhibit considerable cell killing activity against Hh-dependent CSC lines and the reduction of human pancreatic PANC1 and PANC0403 xenograft tumor size, may be beneficial for the treatment of patients with Hh-dependent CSC-driven malignancies [149].
3.2.1.6. Blocking of Epithelial-mesenchymal transition (EMT)
EMT is a multistep, dynamic, and conserved process that is involved in many pathophysiological diseases, including cancer. It causes the development of cancer stem cells in malignancies, which modulates immunogenic phenomena and chemoresistance while also having a negligible therapeutic effect. The EMT controls cell invasion and migration to a secondary site in PDAC-like complex TME and passes through the mesenchymal to epithelial transition (MET), which leads to the formation of metastatic colonization. A variety of humoral factors, including PDGF and EGF, secreted signaling molecules, and cytokines like transforming growth factor (TGF)-β in the TME, can trigger EMT. Although several other EMT-inducing signal transduction pathways are involved to start the EMT, TGF-β signaling is thought to be the main EMT inducer. It has been demonstrated that employing pathway inhibitors, their nano-formulation, or modifying TME to inhibit the EMT can all help to eradicate the many hallmarks of PDAC malignancies.
3.2.1.6.1. Inhibition of WNT/β-catenin Ligand Signaling in PDAC
Wnt signaling regulates the cell growth, proliferation, differentiation, and stemness of PDAC. A protein-protein interaction study reveals the relationship between the two hub genes DKK1 and HMGA2 and Wnt signaling [150]. The nuclear translocation of-catenin and related genes, including cyclin D1, cyclin E, MMP-7, c-myc, and VEGF, are linked to the progression of the cell cycle, EMT, revascularization, and resistance to apoptosis during PC development [151]. Hence, targeting Wnt/β-catenin signaling pathways can be a prominent strategy for the treatment of PC.
Porcupine O-acyltransferase is a promising target for the blocking of Wnt ligand. The enzyme regulates the proper Wnt ligand processing and secretion, assigning its impact to a molecular target. The inactivating mutation in the ring finger protein 43 (RNF43) leads to cellular growth and proliferation, which are dependent on autocrine Wnt ligand signaling, making them more susceptible to therapeutic agent [152]. Inhibition of porcupine interferes with the production of-catenin, which regulates aberrant cell growth. In this regard, the potent porcupine inhibitor ETC-1922159 has shown marked improvement in treating cell cycle arrest, reduction of stem cells, and proliferation of oncogenes for the treatment of PDAC, and further, it is being forwarded for clinical evaluation (NCT02521844). Similarly, the pan-PI3K inhibitor GDC-0941, which inhibits cell growth and intracellular glucose metabolism, has improved the therapeutic effectiveness of ETC-1922159. As a result, the development of RNF43-mutant PC is inhibited ‘in vivo’ xenografts model [153].
Another canonical Wnt signal inhibitor, the monoclonal antibody OMP-18R5, shows specificity in blocking by blocking the binding of Wnt ligands to various frizzled receptors [154] and results in the inhibition of the tumor growth-initiating cells. Additionally, the inhibitor exhibits a synergistic effect in combination with GEM in the pancreatic xenograft mouse model. To inhibit Wnt signaling in patients with metastatic PDAC, Dotan et al. have shown how the recombinant fusion protein ipafricept works in the context of GEM and Abrexane. Only nine patients out of 26 have reacted partially with clinical benefits at a rate of 81%, with a median PFS response time of 5.9 months [155]. Nevertheless, the trial has been terminated due to adverse effects on the bone-toxicity.
Delivering RNAi-triggering oligonucleotides to tumor tissues is made elegantly possible by the effective therapeutic targeting of Wnt/β-catenin using lipid LNPs. The prototype LNP reveals tumor-selective transportation of a Dicer-substrate siRNA targeting CTNNB1, the gene encoding β-catenin, and results in inhibition of an orthotopic patient-derived xenograft (PDX) bearing mice via Wnt-dependent pathways. [156]. In another study, Ghosal et al. have documented the suppression of cancer cells by alginate/chitosan nNPs loaded with frizzled related protein 1 (SFRP1), a naturally occurring Wnt signaling antagonist. sFRP1 and cisplatin combination treatment has exceptional antiproliferative effects on cancer cells [157]. Similarly, delivery of the trimeric trap protein—which carries the extracellular domain of the Fizzled 7 receptor—by cationic lipid-protamine-DNA nanoparticles has been demonstrated to suppress the Wnt5a level with a notable reduction in tumor growth, even when doxorubicin is present in low doses. This therapeutic approach holds promise for reviving immunogenic activity in Tumor environment [158].
3.2.1.6.2. Transforming growth factor-β (TGF-β) pathways
TGF-β1 plays a pivotal role in activation and proliferation of CAFs, making a patho-physical characteristics in developing dysmoplasia and chemoresistance in PDAC microenvironment. Hence, CAFs targeting is considered as a promising platform in inhibition and killing the tumor cells. Feng et al. reported that CREKA peptide decorated and TCM α-mangostin (α-M) loaded biodegradable polymer nanoparticle (CRE-NP (α-M)) has shown superior activity in reduction of ECM production, increasing of tumor vascular normalization and blood perfusion at tumor era, thereby reveals inhibition oftumor growth in the orthotopic tumor model [159]. In another study, salinomycin (SAL) loaded poly (lactic-co-glycolic acid) (PLGA) NPs has shown the overexpression of E-cadherin, β-catenin, and TGF-R in luciferase-transduced AsPC-1 orthotopic tumors and 52% blocking of tumor growth compared to control group [160]. Schlingensiepen et al. have used a mouse orthotopic xenograft model and human PC cells to demonstrate the anticancer effect of trabedersen in the reduction of TGF-2 production. It demonstrates the capacity to block lymph node metastasis, angiogenesis, and cell migration at low IC50 levels without the use of a transfection agent. Its prospective ability to target lymphokine-activated killer (LAK) cells and then reverse the immunosuppression brought on by TGF-2 is another factor supporting its continued use in clinical phase [161]. Similarly, Targeting TRI/II kinase activity with the novel LY2109761 inhibitor has been shown to prevent the cell proliferation, invasion, and metastasis of luciferase-expressing PC cells. Also, its inhibition effect is promoted in the presence of GEM, enabling its potential synergistic effect on prolonged survival with the decreasing of tumor burden as well as liver metastasis in ‘in vivo’ xenografts model [162]. In another clinical study on 102 patients, the synergistic effect of type I transforming growth factor-beta receptor (ALK5) serine/threonine kinase inhibitor and GEM showed an enhanced overall survival with minimum adverse effect compared to that of GEM treatment alone. The additional benefits of Galunisertib are due to the suppression of macrophage inflammatory protein-1-alpha and interferon-gamma-induced protein 10 expression [163]. Captopril is known to be inhibited the TGF-β1-Smad2 related signalling, thereby suppression of ECM deposition. In this regards, CAFs targeted peptide conjugated liposome has demonstrated the preferential penetration of NPs and release of GEM that promotes the deletion of stroma barrier, making its feasibility to reshape the ECM for the targeted drug delivery [164]. In another, delivery of nanoparticles bound albumin (nab)-paclitaxel (commercially known as Abraxane)/GEM in combination with NIS793 is a pan-anti-TGFβ-neutralizing antibody that shows excellent antitumor activity against pancreatic tumor models, leading to further transition in a phase 2 clinical trial for patients with metastatic PDAC (NCT04390763) [165].
Similarly, pH-sensitive poly(amidoamine) clustered nanoparticles (LYiClustersiPD-L1) decorated with TGF-β receptor inhibitors (LY2157299) loaded with siRNA targeting PD-L1 (siPD-L1) have been developed to augment T cell infiltration and cytotoxicity in the acidic PDAC microenvironment by cooperatively inhibiting TGF-β pathway and the PD-1/PD-L1 checkpoint. In addition to suppressing PDL-1 gene expression, NPs have demonstrated systemic release of therapeutic drugs at lower pH values. Furthermore, it demonstrates increased CD8+T cell infiltration into TME and cooperatively supports the suppression of tumor growth in an orthotopic tumor model and a subcutaneous Panc02 xenograft model [166].
3.2.1.6.3. Targeting NOTCH signaling pathways
The Notch signaling system is crucial for cell proliferation, differentiation, and homeostasis in PDAC. After interacting with particular ligands, a number of Notch receptors, such as Notch-1, Notch-2, Notch-3, Notch-4, etc., activate Notch signaling pathways [167]. Further, proteolytic cleavage regulates the secretion of the active fragment, Notch intracellular domain, NICD, which enters the nucleus and consecutively recruits co-activator complex, p300, and results in the activation of various families of Notch target genes such as Akt, cyclin D1, c-myc, COX-2, ERK, MMP-9, mTOR, NF-B, p21, p27, p53, and VEGF etc [168]. As a result, blocking these genes may provide an effective therapeutic platform for the management of Notch-mediated PC. In this context, it has been demonstrated that down-regulating Notch receptor through blocking the Notch pathway in PC cells using either a gamma-secretase (GSI) inhibitor or MRK-003 inhibits proliferation and growth [169]. In vivo studies have led to 50% inhibition of tumor growth, and further co-delivery of MRK-003 with GEM exhibits a significant antitumor effect in PDAC xenografts. In another clinical phase I study, an approach to disrupting Notch signaling using the-secretase inhibitor MK-0752 in combination with GEM has been initiated for the treatment of patients with PDAC [170]. In this study, the combined agents have been administered per OS weekly intravenously on days 1, 8, and 15 to determine their therapeutic efficacy and further proceed with the phase II trial. The pharmacokinetic analysis suggests the optimum dose for MK-0752 AUC (area under the curve) is beyond 1800 mg once weekly with a fruitful tumor response in 19 patients. This study assigns the application of GEM and a secretase inhibitor (MK-0752) with full or single-agent for the recommended phase 2 dose (RP2D).
Recently, exosome-mediated targeting of PDAC tumors has shown excellent antitumor effects via immune cells. Exosomes rich in lipid rafts are capable of enhancing Bax expression and decrease Bcl-2 expressions with the induction of phosphatase and tensin homolog (PTEN) and glycogen synthase kinase (GSK)-3 beta activation. The interaction of NPs with PCs leads to the intranuclear target of Notc-1 signaling through the suppression of hairy and enhancer-of-split homolog-1 (Hes-1) and impairs the function of Notch-1 signaling with decreased number of tumor cells [171].
3.2.1.6.4. Inhibition of Cyclin-dependent kinase (CDK4/6) pathways
Through the G1-S phase transition and its relationship with cyclin D, which controls retinoblastoma protein phosphorylation (pRb), CDK4/6 controls the orderly course of the cell cycle. This also promotes DNA replication and results in pRb becoming dissociated from the E2F transition factor [172]. Therefore, targeting to CDK4/6 to terminate the aberrant cell cycle progress is opened a new opportunity in clinical advances for the treatment of PDAC like metastasis cancer.
TME in PDAC is associated with dysplastic stroma, which makes it difficult to deliver medicine into the intratumoral zone, in contrast to other TME. Therefore, it is recommended to target CDK4/6 inhibition coupled with inhibitors of secondary carcinogenic pathways, such as mTOR, MEK, and TGF-β1. Franco et al. have explained in a study that Cyclin E1 upregulation is associated with resistance and knockdown, which inhibits CDK4/6 and arrests the cell cycle. It demonstrates the inverse link between taxanes and PLK1 inhibitors and CDK4/6 inhibition, but 5-FU and GEM, which are used as chemotherapy, have a synergistic effect on CDK4/6 inhibition by lowering tumor cell growth and preventing Cyclin E1 expression [173]. In a phase I investigation of patients with mPC, combination therapy-based inhibition of CDK4/6 and mTOR utilizing the inhibitors ribociclib and everolimus has revealed a considerable suppression of CDK4/6 gene expression, suggesting its potential use in later stages of clinical translation [174].
Targeting CDK4/6 in PDAC, the method of autophagy inhibitor hydroxychloroquine (HCQ) and CDK4/6 inhibitor palbociclib (PAL) remotely loaded into a nanoformulation has proven to be highly effective in shrinking and destroying PDAC cells through synergistic effects. Furthermore, in a mouse model, this increases the therapeutic efficacy when used with BCL inhibitors [175].
3.2.1.6.5. Inhibition of NF-κB pathways
According to a study, hyaluronic acid (HA) conjugated and decorated co-poly (styrene maleic acid) (HA-SMA) nanomicelles with 3,4-difluorobenzylidene curcumin (CDF, an anticancer drug) have the potential to inhibit CD44 and NF-κβ expression, leading to a significant anticancer effect against CD44+ PC stem-like cells (CSLCs) with the prevention of cell mitigation, proliferation, and invasion [176]. Wei et al. have reported on the therapeutic efficacy of curcumin conjugated cholesterol-hyaluronic acid (CHA) nanogel for targeted delivery to CD44-expressing drug-resistant cancer cells. The nanogel exhibits downregulation of NF-κβ, TNFα, and COX-2 and significant apoptosis of PDAC cells, resulting in a 13-fold suppression of tumor growth as compared to control one [177].
Furthermore, miR-205 administration in combination with therapeutic drugs induces E-cadherin expression, suppresses ZEB1 expression, and reverses the mesenchymal to epithelial transition (MET) in MIA PaCa-2R cells. For the transport of GEM and miR-205 in GEM-resistant MIA PaCa-2R cells, Mondal et al. have demonstrated the formulation of Cetuximab C225 (as EGFR targeting) decorated malemido-poly (ethylene glycol)-block-poly (2-methyl-2-carboxyl-propylene carbonate graft-dodecanol (C225-PEG-PCD). The micellar NPs shows a significant enhancement in EGFR-mediated cellular uptake and inhibition of tumor growth with increased apoptosis and reduced EMT in orthotopic pancreatic tumors bearing NSG mice [178]. The biodegradable micelle with its cationic feature reveals an outstanding capacity for miRNA complexation at a N/P ratio of 4/1 and more than 90% transfection efficiency into GEM-resistant MIA PaCa-2R and CAPAN-1R PC cells. It shows a capability to reverse the chemo-resistance, inhibit migration, and increase apoptosis in the ectopic tumor model [179]. In this context, the transfected miR-205 also results in the suppression of stem cell markers OCT3/4 and CD44 from the ALDH-positive CSC fraction in MIA PaCa-2 cells, as well as the chemoresistance marker class III b-tubulin (TUBB3) [180]. The targeting of plectin-1 decorated chimeric peptide (PL-1)/miR-212 NPs and arginine-rich RNA-binding motifs has been shown to increase the serum stability of miR-212 in RNase and serum. Doxorubicin has a substantial therapeutic effect on PDAC cell autophagy and death through the PL-1/miR-212 nano assembly, and it also inhibits the expression of the USP9X (ubiquitin-specific peptidase 9, X-linked, USP9X) [181].
To target NF-κB signaling pathways, micelles prepared using and hyaluronic acid (HA)-conjugated poly(styrene maleic acid) copolymer (HA-SMA) and loaded with potent anticancer agent 3,4-difluorobenzylidene curcumin showed significant uptake by triple-marker positive (CD44+/CD133+/EpCAM+) pancreatic CSLCs compared with their triple-marker negative (CD44−/CD133−/EpCAM−) counterparts. Further, there was dose-dependent cell killing of MIA PaCa-2 and AsPC-1 cells. Further, it shows a potential reduction of CD44 expression and inhibition of NF-κB signaling with remarkably inhibition of cell proliferation, invasion, and mitigation of CSLCs [176].
NF-κB signaling pathway has been targeted by biomimetic NPs made of naïve neutrophil membrane-coated poly(ethylene glycol) methyl ether-block-poly(lactic-co-glycolic acid) (PEG-PLGA). These NPs have demonstrated the ability to penetrate desmoplastic pancreatic tumor and have inhibited tumor growth in a tumor-bearing mice, with NF-κB, IL-6, and IL-1β being suppressed in NPs/CLT treatment group. Additionally, the treatment group shows a reduction in NIK, TAK1, and Ki67 levels, suggesting that CLT’s substantial therapeutic efficacy in inhibiting NF-κB signaling is effective in treating PDAC [182].
3.2.1.7. Targeting tumor microenvironment (TME)
Targeting PC cells is difficult because of complex pathophysiological features in the TME, such as ECM, CAFs, and immune cells, vascular systems. As a result, reshaping through TME modulation is encouraged as a promising therapeutic approach to get around the stroma barrier. To target and reduce the therapeutic resistance in TME for the treatment of PC, NPs, especially polymeric nanocarriers, have been proposed as an alternative to conventional approaches. Targeting TME entails stopping ECM deposition, obstructing CAFs, resuming immunogenic activities, and preserving hypoxic conditions.
3.2.1.7.1. Targeting Extracellular matrix (ECM)
ECM, which is made up of various macromolecules such as collagen, fibronectin, proteoglycan, HA, and proteases, regulates the integrity of the structure of TME and encourages the invasiveness and cell proliferation of the tumor. Immune cell infiltration and the delivery of therapeutic medicines into the TME are inhibited by the deposition of cellular components. In light of this, targeting ECM and its related receptor molecules may be a promising method for ECM deletion and TME regulation in the therapy of PDAC. All-trans retinoic acid (ATRA), an inducer of PSC quiescence, and siRNA targeting heat shock protein 47 (HSP47), a collagen-specific molecular chaperone, have been created to code for it in order to prone it and restore the activity of PSCs. The nanosystem indicates that PSC quiescence induction suppresses ECM hyperplasia, which leads to promising drug delivery and considerable anticancer efficacy in xenograft PDAC model [183]. Emamzadeh et al. have demonstrated the co-delivery of PTX and GEM through redox-sensitive and thermos-responsive block copolymers with sub-50 nm-sized micelles. The special feature of nanocarriers is that they exhibit maximum loading, followed by controlled release of these drug molecules into the TME, which results in a synergistic effect in the killing of pancreatic cells line [184]. The treatment pathophysiology of TME by targeting hypoxia through triplet combinations, including TH-302, GEM, and Abrexane, has been studied in Hs766t, MIA PaCa-2, PANC-1, and BxPC-3 PDAC xenograft models. The additional therapeutic efficacy of TH-302 against hypoxia-resistant tumor models has shown that it has a synergistic antitumor effect in inhibiting cell proliferation, reducing stromal density, and intratumoral hypoxia, followed by DNA damage, apoptosis, and tumor necrosis as compared to G + nP combination or individual treatment. This study has also influenced the implementation of this combination in clinical phase-1 trail [185]. The survival of PDAC in hypoxia and desmoplasia is regulated by the KRAS-mediated adjustment of pH through the enzyme carbonic anhydrase 9 (CA9) (66% expression in PDAC). The knockdown of CA9 with trametinib or inhibition with SLC-0111 has shown suppression of the posttranscriptional stabilization of HIF1A and HIF2A and reduction of GEM-linked glycolysis in hypoxia conditions. Further, in an in vivo’ study using KrasG12D/Pdx1-Cre/Tp53/RosaYFP genetically modified mice xenograft models, the oral administration of SLC-0111 and injection of GEM have led to enhanced intratumor acidosis, cell death, and reduction of tumor growth and number of B-cells, as well as a longer survival time than that of the control groups [186]. Targeting the CD44 receptor is another interesting method for actively delivering therapeutic compounds into the PDAC microenvironment. GEM and quercetin (QCT) have been combined in a study to show enhanced cellular uptake into PDAC cell lines like MIA-PaCa-2 and PANC-1, leading to a synergistic effect in the prevention of cell migration, cell apoptosis, and anti-inflammatory effects [187].
As a crucial component of the ECM, hyaluronic acid reduces tumor perfusion by increasing the tumor’s interstitial fluid pressure and causing vascular collapse, which promotes cancer growth and spread. Regarding this, targeted with endogenous degradation enzyme, Hyaluronidase (HAase) conjugated biodegradable dextran pH-sensitive polymer NP displays the cleavage of HA to disrupt the ECM structure, which has led to enhancing the permeability of oxygen and therapeutic molecules [188]. Similarly, the therapeutic efficacy of delivering the paclitaxel-loaded liposome has shown significant accumulation and antitumor effects in collagenase-pre-treated PDAC tumors as compared to blank liposome-treated one [189]. In a different investigation, glycerol monostearate-g DSPE-PEG LNPs loaded with GEM and erlotinib (ERL) have been created to target the Type-1 matrix metalloproteinase (MT1-MMP, a modulator of PDAC progression). The post-therapeutic investigation demonstrates sustained plasma stability and effective cellular absorption with possible ‘in vivo’ anticancer efficacy [190]. Similarly, the synthesized cancer stemness inhibitor BBI608-loaded and dexamethasone-PEG-PLA conjugate-based redox-stimuli polymersome has revealed the dilation of the nuclear pore complexes and transports the maximum percentages of reducing agents, which leads to a reduction of 43% of BxPC3 cells viability in a 3D spheroid cultures [191]. Small interfering RNA (siRNA) has been delivered to orthotopic PCrs using cationic perfluorocarbon nanoemulsions as an intraperitoneal delivery platform by Ding et al. When compared to control polycation/siRNA polyplexes, this nanoemulsion’s main job is to modulate the interaction between tumor cells and nerve growth factor (NGF). This is done by suppressing the NGF gene both ‘in vitro’ and ‘in vivo’ PDAC model [192]. Chen et al., have conducted research on the efficiency of PMBOP-CP-based nanocarriers in blocking Xkr8 mRNA by co-delivering FuOXP and Xkr8 short interfering RNA. This approach maximizes tumor ECs-mediated active targeting while reducing liver sinusoidal endothelial cells (LSECs)-mediated absorption. Assigning the therpeutic potential of Xkr8 in combination with chemotherapy for the antitumor effect, it has shown a significant improvement in the tumor immune microenvironment and improved antitumor activity in C57BL/6 mice [193].
3.2.1.7.2. Targeting cancer associated fibroblasts (CAFs)
CAFs are the key component in the formation of tumor stroma and regulate the development and progression of pancreatic cancer through the activation of various signaling pathways, including SHH, TGF, tumor necrosis factor (TNF), IL-1, etc. Therefore, approaches to inhibition of its activation and suppression of its downstream signaling may be the most versatile platform for the treatment of PDAC. Recently, Cun et al. demonstrated the targeting of tumor-associated fibroblast (TAF) by the synthesis of multifunctional and size-switching dendrigraft poly-l-lysine (DGL)/GEM@PP/GA nanoparticles. The DGL nanoparticles exhibit tumor accumulation through MMP-2 overexpression in pancreatic cancer cells. Upon accumulation into TME, the GEM-conjugated small NPs reveal the GEM-mediated killing of tumor cells. Further, residual 18-glycyrrhetinic acid (GA)-loaded large NPs (PP/GA) having lower tumor penetration ability are preferentially uptaken by TAFs and control the secretion of Wnt 16 to trigger the DRP molecule in proceeding the long-term antitumor effect in stroma-rich pancreatic cancer [194]. Targeting overexpressed proteins on CAFs has also been described by Yu et al., in contrast to stromal barrier breaching and depletion. In this instance, CAP (a FAP-responsive cleavable amphiphilic peptide)-decorated, and thermos-sensitive liposomes are used to load the albumin NP of paclitaxel (HSA-PTX), which demonstrates significant tumor penetration ability and sustainable drug release as well as killing of tumor cells under IR-780, a photothermal agent-mediated photothermal irradiation [195]. A novel ligand called the CKAAKN peptide has been employed in targeted nanomedicine to treat pancreatic cancer. Safe intravenous injection of nanoparticles containing the conjugated peptide to squalene (SQCKAAKN) and subsequently co-nanoprecipitated with the squalenoyl prodrug gemcitabine (SQdFdC) is made possible by this ligand-efficient homing device into the TME. The CKAAKN functionalization enables nanoparticles to interact with tumor cells and angiogenic vessels, promoting pericyte coverage and improving tumor accessibility [196]. In another study, lipid-coated protamine DNA complexes loaded with sTRAIL and encoding TNF-related factor has been developed to target the TAF-derived cytotoxic proteins in an orthotopic pancreatic tumor bearing mice. According to a dose-dependent study, nearly 70% of TAFs cells that produce sTRAIL are found to remodel the TME and promote apoptosis, re-educating the remaining fibroblast into a dormant state, demonstrating the ability to cross the desmoplastic barrier with effective anticancer phenomena [197].
3.2.1.7.3. Restoration of immunogenic activity
The immunophenotype of the disease changes because the conversion of healthy pancreatic cells into tumor cells causes tissue fibrosis and increases the number of TAMs, including those with the M2 phenotype, neutrophils with the N2 phenotype, and Tregs. Additionally, T-helper 2 cell-type cytokines encourage the polarization of M1 TAMs toward the M2 phenotype, which results in immunosuppression, tumor development, and metastasis. Gao et al. have created an in situ injectable thermosensitive chitosan hydrogel made of lipid-immune regulatory factor 5 (IRF5) mRNA and C-C chemokine ligand 5 (CCL5) siRNA (LPR) NP complexes (LPR@CHG) in an effort to revive the immunogenic activity in TME. The LPR@CHG hydrogel has been shown to upregulate IRF5 and downregulate CCL5 expression, which exhibits a significant increase in M1-phenotype macrophages, thereby restoring T cell-mediated immune responses in the TME of PDAC [198]. Again, the PI3K and colony stimulating factor-1/colony stimulating factor-1 receptor (CSF-1/CSF-1R) pathways control the infiltration and polarization of immunosuppressive cells like M2 TAMs, which in turn suppresses the tumor immune microenvironment (TIME). To improve the efficiency of M2 TAM targeting, the PI3K-inhibitor NVP-BEZ 235 and CSF-1R-siRNA were co-delivered in a nanomicelle decorated with the M2 TAM targeting peptide, M2pepa. With effective anticancer activity and modification of the TIME, the improved TAM targeting results in a decrease in M2 TAM level and infiltration of myeloid-derived suppressor cells (MDSCs), which has a synergistic effect on inhibiting PI3K- and downregulating CSF-1R [199]. In a different study, cholesterol-modified polymeric CXCR4 antagonist (PCX) and NPS coated with anti-miR-210 and siKRAS has demonstrated significant TME internalization and revealed an orthotopic synergistic impact via inhibition of CXCR4 and downregulation of miR-210 and KRASG12D. Additionally, this has caused PSC growth to be inhibited and cytotoxic T cell infiltration to rise, which has changed the desmoplastic TME [200]. Das et al. have demonstrated how the retinoic acid-inducible gene I (RIG-I)-like receptors can bind to 5’ triphosphate dsRNA (ppp dsRNA) by lipid calcium phosphate NPs and produce type I interferon in the apoptosis of cancer cells by Bcl2 silencing. This leads to the upregulation of pro-inflammatory Th1 cytokine activation and increasing proportions of CD8+ T cells over Treg cells, M1 over M2 macrophages, and a reduction of immunosuppressive B regulatory and plasma cell numbers in the TME [201].
KRASG12D, a key player in pancreatic ductal adenocarcinoma, is a tumor immunity repressor. Recent study has shown that it’s conditional elimination in mice leads to tumor eradication, involving reactivation of FAS, CD8+ T cell-mediated apoptosis and activation of antigen-presenting cells. High KRAS expression in PDAC tumors results in shorter survival, suggesting the potential for KRAS targeting with immunotherapy [202]. Another study explores the effects of inhibiting the KRASG12D mutation with MRTX1133, a small molecule inhibitor, on early and advanced pancreatic adenocarcinomas (PDAC). Results show that MRTX1133 reverses early PDAC growth, increases CD8+ effector T cells, decreases myeloid infiltration, and reprograms cancer-associated fibroblasts. This suggests a synergistic combination of MRTX1133 and immune checkpoint blockade (ICB) for clinical trials [203]. Relaxin (RLN, a systemic hormone) is efficacious in decreasing fibrosis. In a study using a mouse model of pancreatic ductal adenocarcinoma, Zhou et al. have demonstrated that RLN can modulate macrophages, promoting fibrosis depletion and cytotoxic T cell infiltration. This could improve checkpoint immunotherapies’ therapeutic outcomes [204]. Also, Tregs also play a significant role in tumor progression. According to Magliano research group’s investigation, Tregs are a major source of TGF ligands, and depletion of them leads to the reprograming of the fibroblast population with the loss of tumor-restraining, smooth muscle actin-expressing fibroblasts. Additionally, it demonstrates that chemokine production increases recruitment, immunological suppression, carcinogenesis, and pathogenic CD4+ T-cell responses. This shows that fibroblasts are a diverse population with a variety of roles in the development of pancreatic cancer [205]. Similarly, Sun et al. have reported about the antitumor effect of triple drugs, including an immunomodulating agent (NLG919, an inhibitor of indoleamine 2,3-dioxygenase 1 (IDO1)), a chemotherapeutic drug such as PTX, and GEM conjugated via a redox-responsive polymer, PGEM, against PDA tumors. Compared to PGEM or NLG919, PGEM micelles co-loaded with PTX and NLG919 micelles have demonstrated significant penetration into TME, suppression of tumor growth with increasing percentages of CD4+IFNγ+ T and CD8+IFNγ+ T cells, and downregulation of Tregs cells, indicating their synergistic effect on the immunotherpy of PDA tumors [206]. In an investigation by Yang et al., it has been demonstrated that the radiotherapy-augmented Warburg effect in pancreatic cancer leads to immunosuppressive myeloid cells, limiting treatment efficacy. The enhanced immunosuppressive phenotype of myeloid-derived suppressor cells (MDSCs) is due to sustained lactate secretion. Blocking lactate production or deleting HIF-1 in MDSCs effectively inhibits tumor progression. Targeting lactate derived from tumor cells and HIF-1 signaling may hold promise for clinical therapies to alleviate radio-resistance in PDAC [207]. Similar to this, Zhu et al. have shown that blocking myeloid growth factor receptor CSF1R signaling results in the upregulation of T-cell checkpoint molecules, such as PDL1 and CTLA4, which has a limited effect on killing PDAC. However, blocking CSF1R also reveals expression of antigen presentation by the reprogramming of macrophages to enable T-cell mediated antitumor activity. In preclinical PDAC treatment, checkpoint-based immunotherapeutics have the potential to drastically regress tumor growth when combined with CSF1R inhibition and PDL1/CTLA4 antagonists [208]. In addition, a powerful inhibitor of indoleamine-2, 3-dioxygenase (IDO) and a photosensitizer encapsulated in polydopamine (dp-5 or dp-16)-coated NPhave been developed to enhance the effectiveness of immunochemo-photothermal therapy against primary and distal tumors. These multidrug-loaded nanocarriers (N/PGEM/dp-16/5), i.e., GEM, NLG919 (immunomodulating agents), have been developed to work in concert. A greater dp-16 nanocarrier may be capable of photothermal conversion, which would decrease cancers both distant and localized. The late metastatic cancer model has demonstrated an abscopal anticancer effect with considerable tumor cell ruling out, showing the innate and adaptive immune-mediated anticancer therapy [209].
3.2.1.7.4. Targeting Pancreatic Stellate Cells
PSCs and PCCs invade and migrate by upregulating ECM proteins like periostin, glycan binding proteins like galectin-1, and activation markers like α-SMA on the EMT. Additionally, in nutrient-deprived and hypoxic TME, the autophagy of PSCs PCCs results in the removal of amino acids like alanine, which further stimulates lipid synthesis via the TCA cycle. This process also helps PSCs build the stroma [210]. To stop the processes that lead to the advancement of PDAC cancer, it is advised to target PSCs specifically as a customized treatment approach.
PLGA NPs loaded with either indocyanine green (NanoICG) or chloroquine (NanoCQ) are selectively deposited into pancreas, displaying retention for more than seven days post-administration in an orthotopic pancreatic tumor beating mice. The nanosystem has shown that dense desmoplasia can be disrupted even at lower concentrations of CQ by PSC deactivation, and tumor progression suppression in the presence of GEM may hold therapeutic promise in the preclinical phases [211]. When PSCs/PCCs coculture are treated with pirfenidone (PFD, an antifibrotic drug) in addition to GEM, PSC proliferation, invasiveness, and spreading are inhibited, and the G0/G1 cell cycle phase is blocked. In contrast, this is to when PFD or GEM is used alone. In vitro research has shown that exposure to PFD dose-dependently reduces the expression of PDGF, HGF, collagen-1, fibronectin, and periostin by PCSs, whereas untreated supernatant stimulates these secretions. Additionally, the combination of PFD and GEM shows a synergistic effect in reducing the tumor growth and peritoneal disseminated nodules while reversing liver metastasis. This indicates that PFD has preclinical benefits in suppressing desmoplasia by regulating PSCs for treating PDAC [212]. Similar forms of PSC deactivation and tumor-stromal signaling disruption have been reported in the presence of duloxetine, a seroton-innoradrenaline reuptake inhibitor. Research using an in vivo KPC mouse model shows that oral duloxetine administration results in a significant reduction in PDAC cell migration and proliferation as well as a blockade of CAF formation and an anticancer immunoinflammatory impact. Furthermore, atipamezole, a synthetic α2 adrenergic receptor antagonist, when used in conjunction with it shows improvement in pain and survival related to cancer along with delayed appetite loss, cachexia, and body weight reduction [213]. Indometacin, a nonselective COX-2 inhibitor and anti-inflammatory medication, has been shown to reduce PSC proliferation and migration in a dose-dependent manner. The results of immunoblotting and immunofluorescence analysis also show a significant decrease in COX-2 and α-SMA expression after ibumetacin treatment, suggesting that the drug is efficient in inhibiting COX-2 expression to prevent PSC activation [214].
The remodeling of the stroma by the active metabolite of vitamin A, ATRA, reveals PSC reprogramming by restoring mechanical quiescence. ATRA is important in regulating extracellular mechanical forces because it suppresses force-mediated ECM remodeling and inhibits cell invasion and migration in three-dimensional organotypic models. This creates new opportunities for PDAC treatment mediated by stroma-ablation [215]. Delivering GEM and metformin via a pH-low insertion peptide (pHLIP)-based nanocarrier has been shown to dramatically lower TGF-β expression and suppress PSC activation by obstructing the 5′-adenosine monophosphate-activated protein kinase pathway in PANC-1 cells. PSC deactivation further has decreased collagen and α-SMA levels and resulted in 91.2% greater cell growth inhibition when the sequential MET and GEM-MNP-pHLIP therapies are tested on subcutaneous and orthotopic tumor animal models. The novel pancreatic cancer cascade treatment and its inventive application have demonstrated a significantly improved therapeutic efficacy, for example, attaining 91.2% growth inhibition ratio during the course of 30 days of treatment [216]. According to a different study by Farrell et al., the multimodal nanocarrier made of PLGA, polyethyleneimine (PEI), rose bengal (RB), and indocyanine green (ICG) is sensitive to PSC cells and reduces tumor stroma. The prospective impact of sonodynamic therapy (SDT)-based treatment of pancreatic cancer on the suppression of stroma is higher than that of the control group in xenograft and syngeneic preclinical tumor bearing mice [217]. Contrary to PLGA NPs, anti-miR-199a decorated dimeric cell-penetrating peptide NCs have been demonstrated to accumulate more (130 fold) by hPSCs and PCCs (10 fold) than monmeric NCs. This accumulation has also resulted in the reduction of hPSC/PCCs based 3D heterospheroids and the blocking of hPSCs’ differentiation into CAFs, indicating the protumorigenic activity of anti-miRNA loaded delivery system against PSCs [218].
4. Conclusion and future directions
Mechanisms by which the diverse TME components contribute significantly to the onset and progression of PDAC. The abnormal relapse of complex tumor structures and more aggressive tumor cells is caused by the selective reduction of any TME component. In this regard, a combined target for modifying the TME is proposed to weaken the intricate barrier and increase treatment sensitivity. To achieve preclinical benefits, it is also necessary to simultaneously block many stromal cells and reprogram immunogenic activity. As a result, new and versatile therapeutic approaches should be developed for use in combination therapy. The development of intricate tissue barriers, such as desmoplasia, that cause chemoresistance and pose significant challenges in the treatment of PDAC cells, is demonstrated to be connected to metabolic modification and aberrant activation of oncogenic signalling pathways. Although development of novel methods for directly inhibiting front-line oncogenes, such as the KRAS signalling pathway, have been started, genetic mutation leads to poor treatment efficacy in preclinical stages. Targeting of downstream signalling pathways is therefore suggested, and inhibiting the activation of multiple oncogenes at once may be effective in clinical translation. The recent development of receptor-mediated targeted nanomedicines has been found to enhance the rate of preclinical success, in contrast to conventional therapy. It has been thought that developing biocompatible and biodegradable nanocarriers, particularly lipid and polymeric NPs to entrap therapeutic agents is a potent tool for avoiding the pointless loss of drug molecules in serum and getting around the intricate TME shield to effectively transport drug molecules. Additionally, prodrug formulations that are endogenous or responsive to external cues have been shown to boost attraction to maintain drug release while carriers are degrading. One current example is the quest for on-demand smart NPs to control the release of therapeutic medicines with the least amount of harm to healthy tissues. Despite the failure of medication-controlled treatment of PDAC, a thorough understanding of the complicated processes involved in TME and its related signaling molecules gives us the confidence to create a cutting-edge strategy and successfully treat PDAC in clinical stages.
The potential for improved preclinal outcomes, the growing interest in tailored drug delivery, and technological advancements make polymer and lipid NP-based drug administration appear to have a promising future. The development of drug delivery with an active target is one of the main areas of focus. This strategy aims to enhance drug accumulation in target tumor cells while reducing the toxicities associated with off-site treatment. The method for achieving this is to functionalize drug delivery vehicles, such as NPs, with the ligand (targeting moieties) for a specific receptor that is overexpressed in cancer cells, such as folate, integrin, or transferrin. Improved performance of polymer-lipid hybrid NPs in drug delivery applications is another noteworthy accomplishment. These are emerging as a next-generation drug delivery platform. Many benefits are available with them, including as excellent stability, particle size management, and surface functionalization. Dendritic molecules are particularly advantageous since they are highly stable, easy to manipulate particle size and functionalize the surface, which often result in the enhanced aqueous solubility of hydrophobic drugs. Posttranslational modifications have given rise to mRNA-based protein replacement therapies. Ionizable LNPs have the potential to efficiently deliver miRNA to the tumor and enhance the therapeutic efficacy of miRNAs. In preclinical animal models, bioreducible ionizable lipids can be effectively used to deliver CRISPR/Cas9 systems and antisense oligonucleotides. Their uses may be limited by the difficulty of synthesizing ionizable lipids with disulfide bonds and the possibility of premature drug release. Good manufacturing practice (GMP) is essential to ensure drug purity and therapeutic effectiveness as well as factors like safety profiles and storage conditions. Although ionizable LNPs appear to have potential for delivering miRNA for treating pancreatic cancer, more investigation is required to address issues related to their production, premature release, and formulating the particles for particular uses. Adjuvant therapy also includes the fact that antibody-drug conjugates (ADCs) have demonstrated notable anticancer effect in preclinical research. However, more work is needed to overcome the problems related to the selection of tumor antigens and linker molecule, which determines the level and duration of drug release from the ADCs.
Today, pancreatic cancer metabolism research is centered on immunotherapy. The field of immunotherapy is hard and complex when it comes to treating pancreatic cancer. A primary obstacle in pancreatic cancer is the highly immunosuppressive nature of the TME, which makes it more difficult for immune cells to recognize and eradicate tumor cells. Disrupting the network of TME components can also be a viable strategy to control the perfusion and immunogenic activity of medicinal medicines. The inhibitor effect can be synergistically improved and the drug resistance phenomena can potentially be overcome through size-controlled formulation, targeted surface marker targeting, and combinatory therapeutic applications.
Molecular and immunological profiling of PDAC patients ought to be the first considerations when choosing a treatment plan to optimize immunotherapy. Emerging genomic and other biomarker profiles have provided unprecedented opportunities to identify novel targets and strategies to develop personalized therapies. Research on immunotherapy for pancreatic cancer is also greatly advanced by collaborative initiatives, such as the cooperation for clinical trials among the National Cancer Institute (NCI), medical institutions and pharmaceutical companies. In conclusion, for the successful treatment of pancreatic cancer, collaborative research among scientists diverse expertise and practicing physicians is essential and many obstacles can be overcome by the use of effective nanomedicine.
Figure 5.
Evaluation of synergistic effect of small molecule PLK1 inhibitor and miRNA-34a in Orthotopic pancreatic tumor bearing mice. (A) Synthesis scheme and formulation of reactive oxygen species (ROS)-sensitive poly(ethylene glycol)-b-poly[aspartamidoethyl(p-boronobenzyl)diethylammonium bromide (PEG-b-PAEBEA) based nanoassembly for treating pancreatic cancer, (B) Bioluminescence images of tumors and isolated tumor images at the end of the experiment with different formulations (n = 5, *P < 0.05, **P < 0.01, and ***P < 0.001), (C) miR-34a and (D) PLK1 expression level in tumor was determined by PCR assay (n = 3, **P < 0.01 and ***P < 0.001). [Adapted with permission from “Xin et al., ACS Appl. Mater. Interfaces 2019, 11, 14647–14659”. Copyright (2019) American Chemical Society].
Scheme 2.
Schematic representation of different strategies for drug delivery to treat pancreatic cancer.
Highlights.
TME is a complex biological barrier with multiple components, making combination therapy potentially more effective in influencing TME remodeling.
Signaling molecules play a crucial role in metastatic pancreatic cancer cell formation and tissue structure.
Frontline oncogene mutations hinder therapeutic trials; targeting downstream signaling offers advantages in preclinical research.
The unique geometrical characteristics of lipid and polymeric nanoparticles exhibit exceptional performance in loading therapeutic compounds and transporting them via receptors. Stimuli-responsive and PEGylated nanoparticles exhibit excellent therapeutic efficacy against PDAC treatment by preventing the early degradation of drug molecules in plasma and minimizing post-therapeutic genotoxicities.
Acknowledgements
The National Institutes of Health (R01CA266759, R01DK135817, R01NS116037, R01NS128336 and R01CA266759 to RIM) are duly acknowledged for providing financial support for this work.
ABBREVIATIONS
- α-SMA
Alpha smooth muscle actin
- BRACA1/2
breast cancer gene ½
- BRAF
B-Raf proto-oncogene
- BRD4
bromodomain-containing protein 4
- c-Val-Cit-PABC-PNP
maleimidocaproyl-valine-citrulline-p-aminobenzyloxycarbonyl
- CAFs
cancer-associated fibroblasts
- CDK inhibitor
cyclin-dependent kinase inhibitor
- CDKN2A
Cyclin-dependent kinase inhibitor 2A
- COX-2
cyclooxygenase-2
- CPA
cyclopamine
- DMBA
3, 5-dimethyloxybenzyl alcohol
- EGFR
epidermal growth factor receptor
- EPR
enhanced permeability and retention
- ERK
extracellular signal-regulated kinases
- ECM
extracellular matrix
- FGF
fibroblast growth factor
- FGFR2
fibroblast growth factor receptor 2
- GEM
gemcitabine
- GEF
gefitinib
- GPCR
G-protein coupled receptor
- GSH
glutathione
- HA
hyaluronic acid
- HIF1α
hypoxia-inducible factor 1 alpha
- Hh
hedgehog
- IGFR
Insulin-like growth factor receptor
- IFP
interstitial fluid pressure
- JAK
Janus-associated kinase
- KRAS
Kirsten rat sarcoma viral oncogene homolog
- M2-TAMs
M2 tumor-associated macrophages
- MAPK or MEK
mitogen-activated protein kinases
- MDSCs
Myeloid-derived suppressor cells
- MMPs
Matrix metalloproteinases
- MHC-I
major histocompatibility complex-I
- mPEG-g-PCC
methoxy poly(ethylene glycol)-block-poly (2-methyl-2-carboxylpropylene carbonate)
- mPEG-g-P{(asp)-g-GEM-g-DC}
methoxy poly(ethylene glycol)-block-poly(aspartate g-gemcitabine-g-dodecylamine)
- mTOR
Mammalian target of rapamycin
- Nab-paclitaxel
nanoparticles albumin-bound paclitaxel
- NDDS
Novel Drug Delivery Systems
- NF-κB
nuclear factor kappa B
- PC
Pancreatic Cancer
- pAKt
phosphorylation of Akt
- PARPi
poly(ADP-ribose) polymerase inhibitors
- PDAC
Pancreatic ductal adenocarcinoma
- PDGF
Platelet-derived growth factor
- PDGFR
Platelet-derived growth factor receptor
- pERK
phosphorylation of ERK
- PI3Ks
Phosphoinositide 3-kinases
- PKB
protein kinase B (also known as Akt)
- PLC
Phospholipase C
- PSCs
Pancreatic stellate cells
- PTCH1
Patched homolog 1
- RTKs
Receptor tyrosine kinases
- RNF43
Ring finger protein 43
- TGF-β1
Transforming Growth Factor β1
- TME
tumor microenvironments
- TNF
tumor necrosis factor
- TP53
tumor protein p53
- Treg cells
regulatory T cells
- SHH
Sonic hedgehog
- STAT
Signal transducer and activator of transcription
- SMAD4
SMA and MAD-related protein 4
- SUFU
suppressor of fused homolog
- VEGFR
Vvascular endothelial Growth Factor Receptor
Footnotes
Conflict of Interest
Authors declare no conflict of interest.
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References
- [1].Ram Makena M, Gatla H, Verlekar D, Sukhavasi S, Pandey MK, Pramanik KC, Wnt/β-Catenin Signaling: The Culprit in Pancreatic Carcinogenesis and Therapeutic Resistance, Int J Mol Sci. 20 (2019) 4242. 10.3390/ijms20174242. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [2].Post E, Five-Year Pancreatic Cancer Survival Rate Increases to 12%, Pancreatic Cancer Action Network. (2023). https://pancan.org/news/five-year-pancreatic-cancer-survival-rate-increases-to-12/ (accessed July 11, 2023). [Google Scholar]
- [3].Kung H-C, Yu J, Targeted therapy for pancreatic ductal adenocarcinoma: Mechanisms and clinical study, MedComm. 4 (2023) e216. 10.1002/mco2.216. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [4].Neoptolemos JP, Kleeff J, Michl P, Costello E, Greenhalf W, Palmer DH, Therapeutic developments in pancreatic cancer: current and future perspectives, Nat Rev Gastroenterol Hepatol 15 (2018) 333–348. 10.1038/s41575-018-0005-x. [DOI] [PubMed] [Google Scholar]
- [5].Hall WA, Goodman KA, Radiation therapy for pancreatic adenocarcinoma, a treatment option that must be considered in the management of a devastating malignancy, Radiation Oncology. 14 (2019) 114. 10.1186/s13014-019-1277-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [6].Campbell PJ, Yachida S, Mudie LJ, Stephens PJ, Pleasance ED, Stebbings LA, Morsberger LA, Latimer C, McLaren S, Lin M-L, McBride DJ, Varela I, Nik-Zainal SA, Leroy C, Jia M, Menzies A, Butler AP, Teague JW, Griffin CA, Burton J, Swerdlow H, Quail MA, Stratton MR, Iacobuzio-Donahue C, Futreal PA, The patterns and dynamics of genomic instability in metastatic pancreatic cancer, Nature. 467 (2010) 1109–1114. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [7].Xin X, Kumar V, Lin F, Kumar V, Bhattarai R, Bhatt VR, Tan C, Mahato RI, Redox-responsive nanoplatform for codelivery of miR-519c and gemcitabine for pancreatic cancer therapy, Science Advances. 6 (2020) eabd6764. 10.1126/sciadv.abd6764. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [8].Pramanik N, De T, Sharma P, Alakesh A, Jagirdar SK, Rangarajan A, Jhunjhunwala S, Surface-Coated Cerium Nanoparticles to Improve Chemotherapeutic Delivery to Tumor Cells, ACS Omega. 7 (2022) 31651–31657. 10.1021/acsomega.2c00062. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [9].Gupta A, Sharma R, Kuche K, Jain S, Exploring the therapeutic potential of the bioinspired reconstituted high density lipoprotein nanostructures, International Journal of Pharmaceutics. 596 (2021) 120272. 10.1016/j.ijpharm.2021.120272. [DOI] [PubMed] [Google Scholar]
- [10].Shaya J, Kato S, Adashek JJ, Patel H, Fanta PT, Botta GP, Sicklick JK, Kurzrock R, Personalized matched targeted therapy in advanced pancreatic cancer: a pilot cohort analysis, Npj Genom. Med 8 (2023) 1–8. 10.1038/s41525-022-00346-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [11].Karamitopoulou E, Tumour microenvironment of pancreatic cancer: immune landscape is dictated by molecular and histopathological features, Br J Cancer. 121 (2019) 5–14. 10.1038/s41416-019-0479-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [12].Abou Khouzam R, Lehn J-M, Mayr H, Clavien P-A, Wallace MB, Ducreux M, Limani P, Chouaib S, Hypoxia, a Targetable Culprit to Counter Pancreatic Cancer Resistance to Therapy, Cancers (Basel). 15 (2023) 1235. 10.3390/cancers15041235. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [13].Zhu J, Thompson CB, Metabolic regulation of cell growth and proliferation, Nat Rev Mol Cell Biol. 20 (2019) 436–450. 10.1038/s41580-019-0123-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [14].Pavlova NN, Zhu J, Thompson CB, The hallmarks of cancer metabolism: Still emerging, Cell Metabolism. 34 (2022) 355–377. 10.1016/j.cmet.2022.01.007. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [15].Fukunaga A, Miyamoto M, Cho Y, Murakami S, Kawarada Y, Oshikiri T, Kato K, Kurokawa T, Suzuoki M, Nakakubo Y, Hiraoka K, Itoh T, Morikawa T, Okushiba S, Kondo S, Katoh H, CD8+ tumor-infiltrating lymphocytes together with CD4+ tumor-infiltrating lymphocytes and dendritic cells improve the prognosis of patients with pancreatic adenocarcinoma, Pancreas. 28 (2004) e26–31. 10.1097/00006676-200401000-00023. [DOI] [PubMed] [Google Scholar]
- [16].Ren B, Cui M, Yang G, Wang H, Feng M, You L, Zhao Y, Tumor microenvironment participates in metastasis of pancreatic cancer, Mol Cancer. 17 (2018) 108. 10.1186/s12943-018-0858-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [17].Zhang T, Ren Y, Yang P, Wang J, Zhou H, Cancer-associated fibroblasts in pancreatic ductal adenocarcinoma, Cell Death Dis. 13 (2022) 1–11. 10.1038/s41419-022-05351-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [18].Putra A, Alif I, Hamra N, Santosa O, Kustiyah AR, Muhar AM, Lukman K, MSC-released TGF-β regulate α-SMA expression of myofibroblast during wound healing, J Stem Cells Regen Med. 16 (2020) 73–79. 10.46582/jsrm.1602011. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [19].Wu Y, Zhang C, Jiang K, Werner J, Bazhin AV, D’Haese JG, The Role of Stellate Cells in Pancreatic Ductal Adenocarcinoma: Targeting Perspectives, Frontiers in Oncology. 10 (2021). https://www.frontiersin.org/articles/10.3389/fonc.2020.621937 (accessed July 11, 2023). [DOI] [PMC free article] [PubMed] [Google Scholar]
- [20].Tao J, Yang G, Zhou W, Qiu J, Chen G, Luo W, Zhao F, You L, Zheng L, Zhang T, Zhao Y, Targeting hypoxic tumor microenvironment in pancreatic cancer, J Hematol Oncol. 14 (2021) 14. 10.1186/s13045-020-01030-w. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [21].Hao X, Ren Y, Feng M, Wang Q, Wang Y, Metabolic reprogramming due to hypoxia in pancreatic cancer: Implications for tumor formation, immunity, and more, Biomedicine & Pharmacotherapy. 141 (2021) 111798. 10.1016/j.biopha.2021.111798. [DOI] [PubMed] [Google Scholar]
- [22].Dhatchinamoorthy K, Colbert JD, Rock KL, Cancer Immune Evasion Through Loss of MHC Class I Antigen Presentation, Front Immunol. 12 (2021) 636568. 10.3389/fimmu.2021.636568. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [23].Velez-Delgado A, Donahue KL, Brown KL, Du W, Irizarry-Negron V, Menjivar RE, Lasse Opsahl EL, Steele NG, The S, Lazarus J, Sirihorachai VR, Yan W, Kemp SB, Kerk SA, Bollampally M, Yang S, Scales MK, Avritt FR, Lima F, Lyssiotis CA, Rao A, Crawford HC, Bednar F, Frankel TL, Allen BL, Zhang Y, Pasca di Magliano M, Extrinsic KRAS Signaling Shapes the Pancreatic Microenvironment Through Fibroblast Reprogramming, Cell Mol Gastroenterol Hepatol. 13 (2022) 1673–1699. 10.1016/j.jcmgh.2022.02.016. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [24].Thyagarajan A, Alshehri MSA, Miller KLR, Sherwin CM, Travers JB, Sahu RP, Myeloid-Derived Suppressor Cells and Pancreatic Cancer: Implications in Novel Therapeutic Approaches, Cancers (Basel). 11 (2019) 1627. 10.3390/cancers11111627. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [25].Yang S, Liu Q, Liao Q, Tumor-Associated Macrophages in Pancreatic Ductal Adenocarcinoma: Origin, Polarization, Function, and Reprogramming, Frontiers in Cell and Developmental Biology. 8 (2021). https://www.frontiersin.org/articles/10.3389/fcell.2020.607209 (accessed August 9, 2023). [DOI] [PMC free article] [PubMed] [Google Scholar]
- [26].Paudyal R, LoCastro E, Reyngold M, Do RK, Konar AS, Oh JH, Dave A, Yu K, Goodman KA, Shukla-Dave A, Longitudinal Monitoring of Simulated Interstitial Fluid Pressure for Pancreatic Ductal Adenocarcinoma Patients Treated with Stereotactic Body Radiotherapy, Cancers (Basel). 13 (2021) 4319. 10.3390/cancers13174319. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [27].Ho WJ, Jaffee EM, Zheng L, The tumour microenvironment in pancreatic cancer — clinical challenges and opportunities, Nat Rev Clin Oncol. 17 (2020) 527–540. 10.1038/s41571-020-0363-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [28].Burris HA, Moore MJ, Andersen J, Green MR, Rothenberg ML, Modiano MR, Cripps MC, Portenoy RK, Storniolo AM, Tarassoff P, Nelson R, Dorr FA, Stephens CD, Von Hoff DD, Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial, J Clin Oncol. 15 (1997) 2403–2413. 10.1200/JCO.1997.15.6.2403. [DOI] [PubMed] [Google Scholar]
- [29].Von Hoff DD, Ervin T, Arena FP, Chiorean EG, Infante J, Moore M, Seay T, Tjulandin SA, Ma WW, Saleh MN, Harris M, Reni M, Dowden S, Laheru D, Bahary N, Ramanathan RK, Tabernero J, Hidalgo M, Goldstein D, Van Cutsem E, Wei X, Iglesias J, Renschler MF, Increased Survival in Pancreatic Cancer with nab-Paclitaxel plus Gemcitabine, New England Journal of Medicine. 369 (2013) 1691–1703. 10.1056/NEJMoa1304369. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [30].Yang S-H, Chiang N-J, Chiu S-C, Chou W-C, Bai L-Y, Li C-P, Su Y-Y, Chiu T-J, Chuang S-C, Peng C-M, Chan D-C, Chen J-S, Yen C-J, Chen Y-Y, Chiu C-F, Chen L-T, Shan Y-S, The impact of spleen volume on the survival of metastatic pancreatic adenocarcinoma patients receiving nanoliposomal irinotecan, Am J Cancer Res. 12 (2022) 1884–1898. [PMC free article] [PubMed] [Google Scholar]
- [31].Wainberg ZA, Melisi D, Macarulla T, Pazo-Cid R, Chandana SR, De La Fouchardiere C, Dean AP, Kiss I, Lee W, Goetze TO, Van Cutsem E, Paulson AS, Bekaii-Saab TS, Pant S, Hubner R, Xiao Z, Chen H, Benzaghou F, O’Reilly EM, NAPOLI-3: A randomized, open-label phase 3 study of liposomal irinotecan + 5-fluorouracil/leucovorin + oxaliplatin (NALIRIFOX) versus nab-paclitaxel + gemcitabine in treatment-naïve patients with metastatic pancreatic ductal adenocarcinoma (mPDAC)., JCO. 41 (2023) LBA661–LBA661. 10.1200/JCO.2023.41.4_suppl.LBA661. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [32].Ngozi Nwaefulu O, Rao Sagineedu S, Kaisarul Islam M, Stanslas J, Pancreatic cancer treatment with targeted therapies: are we there yet?, Eur Rev Med Pharmacol Sci. 26 (2022) 367–381. 10.26355/eurrev_202201_27861. [DOI] [PubMed] [Google Scholar]
- [33].Hosein AN, Dougan SK, Aguirre AJ, Maitra A, Translational advances in pancreatic ductal adenocarcinoma therapy, Nat Cancer. 3 (2022) 272–286. 10.1038/s43018-022-00349-2. [DOI] [PubMed] [Google Scholar]
- [34].Rosenblum D, Joshi N, Tao W, Karp JM, Peer D, Progress and challenges towards targeted delivery of cancer therapeutics, Nat Commun. 9 (2018) 1410. 10.1038/s41467-018-03705-y. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [35].Pearce AK, O’Reilly RK, Insights into Active Targeting of Nanoparticles in Drug Delivery: Advances in Clinical Studies and Design Considerations for Cancer Nanomedicine, Bioconjugate Chem. 30 (2019) 2300–2311. 10.1021/acs.bioconjchem.9b00456. [DOI] [PubMed] [Google Scholar]
- [36].Ray P, Dutta D, Haque I, Nair G, Mohammed J, Parmer M, Kale N, Orr M, Jain P, Banerjee S, Reindl KM, Mallik S, Kambhampati S, Banerjee SK, Quadir M, pH-Sensitive Nanodrug Carriers for Codelivery of ERK Inhibitor and Gemcitabine Enhance the Inhibition of Tumor Growth in Pancreatic Cancer, Mol. Pharmaceutics 18 (2021) 87–100. 10.1021/acs.molpharmaceut.0c00499. [DOI] [PubMed] [Google Scholar]
- [37].Perumal S, Atchudan R, Lee W, A Review of Polymeric Micelles and Their Applications, Polymers. 14 (2022) 2510. 10.3390/polym14122510. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [38].Chitkara D, Singh S, Kumar V, Danquah M, Behrman SW, Kumar N, Mahato RI, Micellar delivery of cyclopamine and gefitinib for treating pancreatic cancer, Mol Pharm. 9 (2012) 2350–2357. 10.1021/mp3002792. [DOI] [PubMed] [Google Scholar]
- [39].Monteiro PF, Travanut A, Conte C, Alexander C, Reduction-responsive polymers for drug delivery in cancer therapy—Is there anything new to discover?, WIREs Nanomedicine and Nanobiotechnology. 13 (2021) e1678. 10.1002/wnan.1678. [DOI] [PubMed] [Google Scholar]
- [40].Joubert F, Martin L, Perrier S, Pasparakis G, Development of a Gemcitabine-Polymer Conjugate with Prolonged Cytotoxicity against a Pancreatic Cancer Cell Line, ACS Macro Lett. 6 (2017) 535–540. 10.1021/acsmacrolett.7b00160. [DOI] [PubMed] [Google Scholar]
- [41].Alas M, Saghaeidehkordi A, Kaur K, Peptide–Drug Conjugates with Different Linkers for Cancer Therapy, J. Med. Chem. 64 (2021) 216–232. 10.1021/acs.jmedchem.0c01530. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [42].Wu L, Zhang F, Chen X, Wan J, Wang Y, Li T, Wang H, Self-Assembled Gemcitabine Prodrug Nanoparticles Show Enhanced Efficacy against Patient-Derived Pancreatic Ductal Adenocarcinoma, ACS Appl. Mater. Interfaces. 12 (2020) 3327–3340. 10.1021/acsami.9b16209. [DOI] [PubMed] [Google Scholar]
- [43].Chitkara D, Mittal A, Behrman SW, Kumar N, Mahato RI, Self-Assembling, Amphiphilic Polymer–Gemcitabine Conjugate Shows Enhanced Antitumor Efficacy Against Human Pancreatic Adenocarcinoma, Bioconjugate Chem. 24 (2013) 1161–1173. 10.1021/bc400032x. [DOI] [PubMed] [Google Scholar]
- [44].Parveen S, Arjmand F, Tabassum S, Clinical developments of antitumor polymer therapeutics, RSC Adv. 9 (2019) 24699–24721. 10.1039/C9RA04358F. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [45].Jogdeo CM, Panja S, Kanvinde S, Kapoor E, Siddhanta K, Oupický D, Advances in Lipid-Based Codelivery Systems for Cancer and Inflammatory Diseases, Advanced Healthcare Materials. 12 (2023) 2202400. 10.1002/adhm.202202400. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [46].Bulanadi JC, Xue A, Gong X, Bean PA, Julovi SM, de Campo L, Smith RC, Moghaddam MJ, Biomimetic Gemcitabine–Lipid Prodrug Nanoparticles for Pancreatic Cancer, ChemPlusChem. 85 (2020) 1283–1291. 10.1002/cplu.202000253. [DOI] [PubMed] [Google Scholar]
- [47].Réjiba S, Reddy LH, Bigand C, Parmentier C, Couvreur P, Hajri A, Squalenoyl gemcitabine nanomedicine overcomes the low efficacy of gemcitabine therapy in pancreatic cancer, Nanomedicine: Nanotechnology, Biology and Medicine. 7 (2011) 841–849. 10.1016/j.nano.2011.02.012. [DOI] [PubMed] [Google Scholar]
- [48].Alhussan A, Jackson N, Eaton S, Santos ND, Barta I, Zaifman J, Chen S, Tam YYC, Krishnan S, Chithrani DB, Lipid-Nanoparticle-Mediated Delivery of Docetaxel Prodrug for Exploiting Full Potential of Gold Nanoparticles in the Treatment of Pancreatic Cancer, Cancers. 14 (2022) 6137. 10.3390/cancers14246137. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [49].Shi L, Wu X, Li T, Wu Y, Song L, Zhang W, Yin L, Wu Y, Han W, Yang Y, An esterase-activatable prodrug formulated liposome strategy: potentiating the anticancer therapeutic efficacy and drug safety, Nanoscale Adv. 4 (2022) 952–966. 10.1039/D1NA00838B. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [50].Wang Y, Fan W, Dai X, Katragadda U, Mckinley D, Teng Q, Tan C, Enhanced Tumor Delivery of Gemcitabine via PEG-DSPE/TPGS Mixed Micelles, Mol. Pharmaceutics 11 (2014) 1140–1150. 10.1021/mp4005904. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [51].Coppens E, Desmaële D, Mougin J, Tusseau-Nenez S, Couvreur P, Mura S, Gemcitabine Lipid Prodrugs: The Key Role of the Lipid Moiety on the Self-Assembly into Nanoparticles, Bioconjugate Chem. 32 (2021) 782–793. 10.1021/acs.bioconjchem.1c00051. [DOI] [PubMed] [Google Scholar]
- [52].Xin X, Lin F, Wang Q, Yin L, Mahato RI, ROS-Responsive Polymeric Micelles for Triggered Simultaneous Delivery of PLK1 Inhibitor/miR-34a and Effective Synergistic Therapy in Pancreatic Cancer, ACS Appl. Mater. Interfaces. 11 (2019) 14647–14659. 10.1021/acsami.9b02756. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [53].Ahn J, Miura Y, Yamada N, Chida T, Liu X, Kim A, Sato R, Tsumura R, Koga Y, Yasunaga M, Nishiyama N, Matsumura Y, Cabral H, Kataoka K, Antibody fragment-conjugated polymeric micelles incorporating platinum drugs for targeted therapy of pancreatic cancer, Biomaterials. 39 (2015) 23–30. 10.1016/j.biomaterials.2014.10.069. [DOI] [PubMed] [Google Scholar]
- [54].Kulkarni P, Haldar MK, You S, Choi Y, Mallik S, Hypoxia-Responsive Polymersomes for Drug Delivery to Hypoxic Pancreatic Cancer Cells, Biomacromolecules. 17 (2016) 2507–2513. 10.1021/acs.biomac.6b00350. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [55].Feng Q, Tong R, Anticancer nanoparticulate polymer-drug conjugate, Bioengineering & Translational Medicine. 1 (2016) 277–296. 10.1002/btm2.10033. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [56].Quintana JM, Arboleda D, Hu H, Scott E, Luthria G, Pai S, Parangi S, Weissleder R, Miller MA, Radiation Cleaved Drug-Conjugate Linkers Enable Local Payload Release, Bioconjugate Chem. 33 (2022) 1474–1484. 10.1021/acs.bioconjchem.2c00174. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [57].Bourillon L, Bourgier C, Gaborit N, Garambois V, Llès E, Zampieri A, Ogier C, Jarlier M, Radosevic-Robin N, Orsetti B, Delpech H, Theillet C, Colombo P-E, Azria D, Pèlegrin A, Larbouret C, Chardès T, An auristatin-based antibody-drug conjugate targeting HER3 enhances the radiation response in pancreatic cancer, International Journal of Cancer. 145 (2019) 1838–1851. 10.1002/ijc.32273. [DOI] [PubMed] [Google Scholar]
- [58].Melamed JR, Yerneni SS, Arral ML, LoPresti ST, Chaudhary N, Sehrawat A, Muramatsu H, Alameh M-G, Pardi N, Weissman D, Gittes GK, Whitehead KA, Ionizable lipid nanoparticles deliver mRNA to pancreatic β cells via macrophage-mediated gene transfer, Science Advances. 9 (2023) eade1444. 10.1126/sciadv.ade1444. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [59].Gokita K, Inoue J, Ishihara H, Kojima K, Inazawa J, Therapeutic Potential of LNP-Mediated Delivery of miR-634 for Cancer Therapy, Molecular Therapy - Nucleic Acids. 19 (2020) 330–338. 10.1016/j.omtn.2019.10.045. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [60].Liu L, Xiao X, Guo J, Wang J, Liu S, Wang M, Peng Q, Jiang N, Aptamer and Peptide-Engineered Polydopamine Nanospheres for Target Delivery and Tumor Perfusion in Synergistic Chemo-Phototherapy of Pancreatic Cancer, ACS Appl. Mater. Interfaces. 15 (2023) 16539–16551. 10.1021/acsami.3c01967. [DOI] [PubMed] [Google Scholar]
- [61].Zhao W, Yang S, Li C, Li F, Pang H, Xu G, Wang Y, Cong M, Amphiphilic Dendritic Nanomicelle-Mediated Delivery of Gemcitabine for Enhancing the Specificity and Effectiveness, IJN. 17 (2022) 3239–3249. 10.2147/IJN.S371775. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [62].Wang G, Zhou Z, Zhao Z, Li Q, Wu Y, Yan S, Shen Y, Huang P, Enzyme-Triggered Transcytosis of Dendrimer–Drug Conjugate for Deep Penetration into Pancreatic Tumors, ACS Nano. 14 (2020) 4890–4904. 10.1021/acsnano.0c00974. [DOI] [PubMed] [Google Scholar]
- [63].Rémond MS, Pellat A, Brezault C, Dhooge M, Coriat R, Are targeted therapies or immunotherapies effective in metastatic pancreatic adenocarcinoma?, ESMO Open. 7 (2022) 100638. 10.1016/j.esmoop.2022.100638. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [64].Macdonald JS, McCoy S, Whitehead RP, Iqbal S, Wade JL, Giguere JK, Abbruzzese JL, A phase II study of farnesyl transferase inhibitor R115777 in pancreatic cancer: a Southwest oncology group (SWOG 9924) study, Invest New Drugs. 23 (2005) 485–487. 10.1007/s10637-005-2908-y. [DOI] [PubMed] [Google Scholar]
- [65].KRASG12C Inhibition with Sotorasib in Advanced Solid Tumors | NEJM, (n.d.). https://www.nejm.org/doi/10.1056/NEJMoa1917239?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200pubmed (accessed August 12, 2023). [DOI] [PMC free article] [PubMed] [Google Scholar]
- [66].Chung V, McDonough S, Philip PA, Cardin D, Wang-Gillam A, Hui L, Tejani MA, Seery TE, Dy IA, Al Baghdadi T, Hendifar AE, Doyle LA, Lowy AM, Guthrie KA, Blanke CD, Hochster HS, Effect of Selumetinib and MK-2206 vs Oxaliplatin and Fluorouracil in Patients With Metastatic Pancreatic Cancer After Prior Therapy: SWOG S1115 Study Randomized Clinical Trial, JAMA Oncol. 3 (2017) 516–522. 10.1001/jamaoncol.2016.5383. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [67].Kemp SB, Cheng N, Markosyan N, Sor R, Kim I-K, Hallin J, Shoush J, Quinones L, Brown NV, Bassett JB, Joshi N, Yuan S, Smith M, Vostrejs WP, Perez-Vale KZ, Kahn B, Mo F, Donahue TR, Radu CG, Clendenin C, Christensen JG, Vonderheide RH, Stanger BZ, Efficacy of a Small-Molecule Inhibitor of KrasG12D in Immunocompetent Models of Pancreatic Cancer, Cancer Discovery. 13 (2023) 298–311. 10.1158/2159-8290.CD-22-1066. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [68].Kim D, Herdeis L, Rudolph D, Zhao Y, Böttcher J, Vides A, Ayala-Santos CI, Pourfarjam Y, Cuevas-Navarro A, Xue JY, Mantoulidis A, Bröker J, Wunberg T, Schaaf O, Popow J, Wolkerstorfer B, Kropatsch KG, Qu R, de Stanchina E, Sang B, Li C, McConnell DB, Kraut N, Lito P, Pan-KRAS inhibitor disables oncogenic signalling and tumour growth, Nature. 619 (2023) 160–166. 10.1038/s41586-023-06123-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [69].McAndrews KM, Xiao F, Chronopoulos A, LeBleu VS, Kugeratski FG, Kalluri R, Exosome-mediated delivery of CRISPR/Cas9 for targeting of oncogenic KrasG12D in pancreatic cancer, Life Sci Alliance. 4 (2021) e202000875. 10.26508/lsa.202000875. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [70].Liu X, Ghosh D, Intracellular nanoparticle delivery by oncogenic KRAS-mediated macropinocytosis, Int J Nanomedicine. 14 (2019) 6589–6600. 10.2147/IJN.S212861. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [71].Dou L, Liu H, Wang K, Liu J, Liu L, Ye J, Wang R, Deng H, Qian F, Albumin binding revitalizes NQO1 bioactivatable drugs as novel therapeutics for pancreatic cancer, J Control Release. 349 (2022) 876–889. 10.1016/j.jconrel.2022.07.033. [DOI] [PubMed] [Google Scholar]
- [72].Huang Y, Chen Y, Zhou S, Xie L, Liang K, Xu J, Zhang Q, Chen H, Wang D, Song Q, Jiang G, Mei N, Ma F, Lu H, Gao X, Chen J, Synthetically Lethal Biomimetic Nutri-hijacker Hitchhikes and Reprograms KRAS Mutation-Driven Metabolic Addictions for Pancreatic Ductal Adenocarcinoma Treatment, ACS Nano. 17 (2023) 14014–14031. 10.1021/acsnano.3c04069. [DOI] [PubMed] [Google Scholar]
- [73].Zhao X, Li F, Li Y, Wang H, Ren H, Chen J, Nie G, Hao J, Co-delivery of HIF1α siRNA and gemcitabine via biocompatible lipid-polymer hybrid nanoparticles for effective treatment of pancreatic cancer, Biomaterials. 46 (2015) 13–25. 10.1016/j.biomaterials.2014.12.028. [DOI] [PubMed] [Google Scholar]
- [74].Gilles M-E, Hao L, Huang L, Rupaimoole R, Lopez-Casas PP, Pulver E, Jeong JC, Muthuswamy SK, Hidalgo M, Bhatia SN, Slack FJ, Personalized RNA Medicine for Pancreatic Cancer, Clinical Cancer Research. 24 (2018) 1734–1747. 10.1158/1078-0432.CCR-17-2733. [DOI] [PubMed] [Google Scholar]
- [75].Strand MS, Krasnick BA, Pan H, Zhang X, Bi Y, Brooks C, Wetzel C, Sankpal N, Fleming T, Goedegebuure SP, DeNardo DG, Gillanders WE, Hawkins WG, Wickline SA, Fields RC, Precision delivery of RAS-inhibiting siRNA to KRAS driven cancer via peptide-based nanoparticles, Oncotarget. 10 (2019) 4761–4775. 10.18632/oncotarget.27109. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [76].Pereira SS, Monteiro MP, Costa MM, Ferreira J, Alves MG, Oliveira PF, Jarak I, Pignatelli D, MAPK/ERK pathway inhibition is a promising treatment target for adrenocortical tumors, Journal of Cellular Biochemistry. 120 (2019) 894–906. 10.1002/jcb.27451. [DOI] [PubMed] [Google Scholar]
- [77].Van Cutsem E, Hidalgo M, Canon J-L, Macarulla T, Bazin I, Poddubskaya E, Manojlovic N, Radenkovic D, Verslype C, Raymond E, Cubillo A, Schueler A, Zhao C, Hammel P, Phase I/II trial of pimasertib plus gemcitabine in patients with metastatic pancreatic cancer, Int J Cancer. 143 (2018) 2053–2064. 10.1002/ijc.31603. [DOI] [PubMed] [Google Scholar]
- [78].Gershenson DM, Miller A, Brady W, Paul J, Carty K, Rodgers W, Millan D, Coleman RL, Moore KN, Banerjee S, Connolly K, Secord AA, O’Malley DM, Dorigo O, Gaillard S, Gabra H, Hanjani P, Huang H, Wenzel L, Gourley C, LBA61 - A randomized phase II/III study to assess the efficacy of trametinib in patients with recurrent or progressive low-grade serous ovarian or peritoneal cancer, Annals of Oncology. 30 (2019) v897–v898. 10.1093/annonc/mdz394.058. [DOI] [Google Scholar]
- [79].Weekes C, Lockhart A, LoRusso P, Murray E, Park E, Tagen M, Singh J, Sarkar I, Mueller L, Dokainish H, Shapiro G, Burris H, A Phase Ib Study to Evaluate the MEK Inhibitor Cobimetinib in Combination with the ERK1/2 Inhibitor GDC-0994 in Patients with Advanced Solid Tumors, Oncologist. 25 (2020) 833–e1438. 10.1634/theoncologist.2020-0292. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [80].Thakkar A, Chenreddy S, Wang J, Prabhu S, Ferulic acid combined with aspirin demonstrates chemopreventive potential towards pancreatic cancer when delivered using chitosan-coated solid-lipid nanoparticles, Cell & Bioscience. 5 (2015) 46. 10.1186/s13578-015-0041-y. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [81].Ghafaripour H, Homayouni Tabrizi M, Karimi E, Barati Naeeni N, Lawsone encapsulated polylactic-co-glycolic acid nanoparticles modified with chitosan-folic acid successfully inhibited cell growth and triggered apoptosis in Panc-1 cancer cells, IET Nanobiotechnol. (2023). 10.1049/nbt2.12139. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [82].Yang Y, Li S, Wang Y, Zhao Y, Li Q, Protein tyrosine kinase inhibitor resistance in malignant tumors: molecular mechanisms and future perspective, Sig Transduct Target Ther. 7 (2022) 1–36. 10.1038/s41392-022-01168-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [83].Yang H-H, Liu J-W, Lee J-H, Harn H-J, Chiou T-W, Pancreatic Adenocarcinoma Therapeutics Targeting RTK and TGF Beta Receptor, International Journal of Molecular Sciences. 22 (2021) 8125. 10.3390/ijms22158125. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [84].Adnane L, Trail PA, Taylor I, Wilhelm SM, Sorafenib (BAY 43-9006, Nexavar®), a Dual-Action Inhibitor That Targets RAF/MEK/ERK Pathway in Tumor Cells and Tyrosine Kinases VEGFR/PDGFR in Tumor Vasculature, in: Methods in Enzymology, Academic Press, 2006: pp. 597–612. 10.1016/S0076-6879(05)07047-3. [DOI] [PubMed] [Google Scholar]
- [85].Gonçalves A, Gilabert M, François E, Dahan L, Perrier H, Lamy R, Re D, Largillier R, Gasmi M, Tchiknavorian X, Esterni B, Genre D, Moureau-Zabotto L, Giovannini M, Seitz J-F, Delpero J-R, Turrini O, Viens P, Raoul J-L, BAYPAN study: a double-blind phase III randomized trial comparing gemcitabine plus sorafenib and gemcitabine plus placebo in patients with advanced pancreatic cancer, Ann Oncol. 23 (2012) 2799–2805. 10.1093/annonc/mds135. [DOI] [PubMed] [Google Scholar]
- [86].Zhu M, Zhou L, Hu S, Miao Q, Gong J, Zhang N, Zhang G, Wang M, Wang J, He H, Wang Y, Rational Design and Systemic Appraisal of an EGFR-Targeting Antibody–Drug Conjugate LR-DM1 for Pancreatic Cancer, J. Med. Chem. 65 (2022) 7141–7153. 10.1021/acs.jmedchem.1c01920. [DOI] [PubMed] [Google Scholar]
- [87].Renaldi K, Simadibrata M, Rahadiani N, Handjari DR, Harahap AR, Harimurti K, Zubir N, Siregar L, Loho IM, Suzanna E, Prawirodihardjo B, Hidajat H, Widodo B, Rahniayu A, Tambun R, William A, Makmun D, The Expressions of NF-κB, COX-2, Sp1, and c-Jun in Pancreatic Ductal Adenocarcinoma and Their Associations with Patient Survival, Pathophysiology. 30 (2023) 92–109. 10.3390/pathophysiology30020009. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [88].Wang JP, Wu C-Y, Yeh Y-C, Shyr Y-M, Wu Y-Y, Kuo C-Y, Hung Y-P, Chen M-H, Lee W-P, Luo J-C, Chao Y, Li C-P, Erlotinib is effective in pancreatic cancer with epidermal growth factor receptor mutations: a randomized, open-label, prospective trial, Oncotarget. 6 (2015) 18162–18173. 10.18632/oncotarget.4216. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [89].Mondal G, Kumar V, Shukla SK, Singh PK, Mahato RI, EGFR-Targeted Polymeric Mixed Micelles Carrying Gemcitabine for Treating Pancreatic Cancer, Biomacromolecules. 17 (2016) 301–313. 10.1021/acs.biomac.5b01419. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [90].Le UM, Hartman A, Pillai G, Enhanced selective cellular uptake and cytotoxicity of epidermal growth factor-conjugated liposomes containing curcumin on EGFR-overexpressed pancreatic cancer cells, Journal of Drug Targeting. 26 (2018) 676–683. 10.1080/1061186X.2017.1408114. [DOI] [PubMed] [Google Scholar]
- [91].Singh A, Xu J, Mattheolabakis G, Amiji M, EGFR-targeted gelatin nanoparticles for systemic administration of gemcitabine in an orthotopic pancreatic cancer model, Nanomedicine: Nanotechnology, Biology and Medicine. 12 (2016) 589–600. 10.1016/j.nano.2015.11.010. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [92].Xu J, Gattacceca F, Amiji M, Biodistribution and Pharmacokinetics of EGFR-Targeted Thiolated Gelatin Nanoparticles Following Systemic Administration in Pancreatic Tumor-Bearing Mice, Mol Pharm. 10 (2013) 2031–2044. 10.1021/mp400054e. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [93].Li W, Liu Z, Li C, Li N, Fang L, Chang J, Tan J, Radionuclide therapy using 131I-labeled anti-epidermal growth factor receptor-targeted nanoparticles suppresses cancer cell growth caused by EGFR overexpression, J Cancer Res Clin Oncol. 142 (2016) 619–632. 10.1007/s00432-015-2067-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [94].Du C, Qi Y, Zhang Y, Wang Y, Zhao X, Min H, Han X, Lang J, Qin H, Shi Q, Zhang Z, Tian X, Anderson GJ, Zhao Y, Nie G, Yang Y, Epidermal Growth Factor Receptor-Targeting Peptide Nanoparticles Simultaneously Deliver Gemcitabine and Olaparib To Treat Pancreatic Cancer with Breast Cancer 2 (BRCA2) Mutation, ACS Nano. 12 (2018) 10785–10796. 10.1021/acsnano.8b01573. [DOI] [PubMed] [Google Scholar]
- [95].Ceci C, Atzori MG, Lacal PM, Graziani G, Role of VEGFs/VEGFR-1 Signaling and its Inhibition in Modulating Tumor Invasion: Experimental Evidence in Different Metastatic Cancer Models, Int J Mol Sci. 21 (2020) 1388. 10.3390/ijms21041388. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [96].Doi Y, Yashiro M, Yamada N, Amano R, Noda S, Hirakawa K, VEGF-A/VEGF-R-2 Signaling Plays an Important Role for the Motility of Pancreas Cancer Cells, Ann Surg Oncol. 19 (2012) 2733–2743. 10.1245/s10434-011-2181-6. [DOI] [PubMed] [Google Scholar]
- [97].Tai C-J, Huang M-T, Wu C-H, Wang C-K, Tai C-J, Chang C-C, Hsieh C-I, Chang Y-J, Wu C-J, Kuo L-J, Wei P-L, Chen R-J, Chiou H-Y, Combination of Two Targeted Medications (Bevacizumab Plus Cetuximab) Improve the Therapeutic Response of Pancreatic Carcinoma, Medicine. 95 (2016) e3259. 10.1097/MD.0000000000003259. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [98].Van Cutsem E, Vervenne WL, Bennouna J, Humblet Y, Gill S, Van Laethem J-L, Verslype C, Scheithauer W, Shang A, Cosaert J, Moore MJ, Phase III Trial of Bevacizumab in Combination With Gemcitabine and Erlotinib in Patients With Metastatic Pancreatic Cancer, JCO. 27 (2009) 2231–2237. 10.1200/JCO.2008.20.0238. [DOI] [PubMed] [Google Scholar]
- [99].Ahn HK, Choi JY, Kim K-M, Kim H, Choi S-H, Park SH, Park JO, Lim HY, Kang WK, Lee J, Park YS, Phase II study of pazopanib monotherapy in metastatic gastroenteropancreatic neuroendocrine tumours, Br J Cancer. 109 (2013) 1414–1419. 10.1038/bjc.2013.470. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [100].Spring BQ, Bryan Sears R, Zheng LZ, Mai Z, Watanabe R, Sherwood ME, Schoenfeld DA, Pogue BW, Pereira SP, Villa E, Hasan T, A photoactivable multi-inhibitor nanoliposome for tumour control and simultaneous inhibition of treatment escape pathways, Nature Nanotech. 11 (2016) 378–387. 10.1038/nnano.2015.311. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [101].Leach A, Smyth P, Ferguson L, Steven J, Greene MK, Branco CM, McCann AP, Porter A, Barelle CJ, Scott CJ, Anti-DLL4 VNAR targeted nanoparticles for targeting of both tumour and tumour associated vasculature, Nanoscale. 12 (2020) 14751–14763. 10.1039/D0NR02962A. [DOI] [PubMed] [Google Scholar]
- [102].Wang P, Mak VCY, Cheung LWT, Drugging IGF-1R in cancer: New insights and emerging opportunities, Genes & Diseases. 10 (2023) 199–211. 10.1016/j.gendis.2022.03.002. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [103].Mutgan AC, Besikcioglu HE, Wang S, Friess H, Ceyhan GO, Demir IE, Insulin/IGF-driven cancer cell-stroma crosstalk as a novel therapeutic target in pancreatic cancer, Mol Cancer. 17 (2018) 66. 10.1186/s12943-018-0806-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [104].Kindler HL, Richards DA, Garbo LE, Garon EB, Stephenson JJ, Rocha-Lima CM, Safran H, Chan D, Kocs DM, Galimi F, McGreivy J, Bray SL, Hei Y, Feigal EG, Loh E, Fuchs CS, A randomized, placebo-controlled phase 2 study of ganitumab (AMG 479) or conatumumab (AMG 655) in combination with gemcitabine in patients with metastatic pancreatic cancer, Ann Oncol. 23 (2012) 2834–2842. 10.1093/annonc/mds142. [DOI] [PubMed] [Google Scholar]
- [105].Kundranda M, Gracian AC, Zafar SF, Meiri E, Bendell J, Algül H, Rivera F, Ahn ER, Watkins D, Pelzer U, Charu V, Zalutskaya A, Kuesters G, Pipas JM, Santillana S, Askoxylakis V, Ko AH, Randomized, double-blind, placebo-controlled phase II study of istiratumab (MM-141) plus nab-paclitaxel and gemcitabine versus nab-paclitaxel and gemcitabine in front-line metastatic pancreatic cancer (CARRIE), Annals of Oncology. 31 (2020) 79–87. 10.1016/j.annonc.2019.09.004. [DOI] [PubMed] [Google Scholar]
- [106].Awasthi N, Zhang C, Schwarz AM, Hinz S, Schwarz MA, Schwarz RE, Enhancement of nab-paclitaxel antitumor activity through addition of multitargeting antiangiogenic agents in experimental pancreatic cancer, Mol Cancer Ther. 13 (2014) 1032–1043. 10.1158/1535-7163.MCT-13-0361. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [107].Cantley LC, The phosphoinositide 3-kinase pathway, Science. 296 (2002) 1655–1657. 10.1126/science.296.5573.1655. [DOI] [PubMed] [Google Scholar]
- [108].Jazirehi AR, Wenn PB, Damavand M, Therapeutic implications of targeting the PI3Kinase/AKT/mTOR signaling module in melanoma therapy, Am J Cancer Res. 2 (2012) 178–191. [PMC free article] [PubMed] [Google Scholar]
- [109].Mehra S, Deshpande N, Nagathihalli N, Targeting PI3K Pathway in Pancreatic Ductal Adenocarcinoma: Rationale and Progress, Cancers. 13 (2021) 4434. 10.3390/cancers13174434. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [110].Wang Y, Kuramitsu Y, Baron B, Kitagawa T, Tokuda K, Akada J, Maehara S-I, Maehara Y, Nakamura K, PI3K inhibitor LY294002, as opposed to wortmannin, enhances AKT phosphorylation in gemcitabine-resistant pancreatic cancer cells, Int J Oncol. 50 (2017) 606–612. 10.3892/ijo.2016.3804. [DOI] [PubMed] [Google Scholar]
- [111].Hu C, Dadon T, Chenna V, Yabuuchi S, Bannerji R, Booher R, Strack P, Azad N, Nelkin BD, Maitra A, Combined Inhibition of Cyclin-Dependent Kinases (Dinaciclib) and AKT (MK-2206) Blocks Pancreatic Tumor Growth and Metastases in Patient-Derived Xenograft Models, Mol Cancer Ther. 14 (2015) 1532–1539. 10.1158/1535-7163.MCT-15-0028. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [112].Hopkins BD, Pauli C, Du X, Wang DG, Li X, Wu D, Amadiume SC, Goncalves MD, Hodakoski C, Lundquist MR, Bareja R, Ma Y, Harris EM, Sboner A, Beltran H, Rubin MA, Mukherjee S, Cantley LC, Suppression of insulin feedback enhances the efficacy of PI3K inhibitors, Nature. 560 (2018) 499–503. 10.1038/s41586-018-0343-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [113].Cao P, Maira S-M, García-Echeverría C, Hedley DW, Activity of a novel, dual PI3-kinase/mTor inhibitor NVP-BEZ235 against primary human pancreatic cancers grown as orthotopic xenografts, Br J Cancer. 100 (2009) 1267–1276. 10.1038/sj.bjc.6604995. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [114].Gonzalez-Valdivieso J, Garcia-Sampedro A, Hall AR, Girotti A, Arias FJ, Pereira SP, Acedo P, Smart Nanoparticles as Advanced Anti-Akt Kinase Delivery Systems for Pancreatic Cancer Therapy, ACS Appl. Mater. Interfaces. 13 (2021) 55790–55805. 10.1021/acsami.1c14592. [DOI] [PubMed] [Google Scholar]
- [115].Sharma NK, Shankar S, Srivastava RK, STAT3 as an emerging molecular target in pancreatic cancer, GICTT. 4 (2014) 115–122. 10.2147/GICTT.S48993. [DOI] [Google Scholar]
- [116].Johnson DE, O’Keefe RA, Grandis JR, Targeting the IL-6/JAK/STAT3 signalling axis in cancer, Nat Rev Clin Oncol. 15 (2018) 234–248. 10.1038/nrclinonc.2018.8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [117].Hurwitz HI, Uppal N, Wagner SA, Bendell JC, Beck JT, Wade SM, Nemunaitis JJ, Stella PJ, Pipas JM, Wainberg ZA, Manges R, Garrett WM, Hunter DS, Clark J, Leopold L, Sandor V, Levy RS, Randomized, Double-Blind, Phase II Study of Ruxolitinib or Placebo in Combination With Capecitabine in Patients With Metastatic Pancreatic Cancer for Whom Therapy With Gemcitabine Has Failed, JCO. 33 (2015) 4039–4047. 10.1200/JCO.2015.61.4578. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [118].Komar HM, Serpa G, Kerscher C, Schwoegl E, Mace TA, Jin M, Yang M-C, Chen C-S, Bloomston M, Ostrowski MC, Hart PA, Conwell DL, Lesinski GB, Inhibition of Jak/STAT signaling reduces the activation of pancreatic stellate cells in vitro and limits caerulein-induced chronic pancreatitis in vivo, Sci Rep. 7 (2017) 1787. 10.1038/s41598-017-01973-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [119].Chen P, Huang L, Zhang Y, Qiao M, Yao W, Yuan Y, The antagonist of the JAK-1/STAT-1 signaling pathway improves the severity of cerulein-stimulated pancreatic injury via inhibition of NF-κB activity, International Journal of Molecular Medicine. 27 (2011) 731–738. 10.3892/ijmm.2011.632. [DOI] [PubMed] [Google Scholar]
- [120].Perusina Lanfranca M, Zhang Y, Girgis A, Kasselman S, Lazarus J, Kryczek I, Delrosario L, Rhim A, Koneva L, Sartor M, Sun L, Halbrook C, Nathan H, Shi J, Crawford HC, Pasca di Magliano M, Zou W, Frankel TL, Interleukin 22 Signaling Regulates Acinar Cell Plasticity to Promote Pancreatic Tumor Development in Mice, Gastroenterology. 158 (2020) 1417–1432.e11. 10.1053/j.gastro.2019.12.010. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [121].Seol MA, Kim J-H, Oh K, Kim G, Seo MW, Shin Y-K, Sim JH, Shin HM, Seo BY, Lee D-S, Ku J-L, Han I, Kang I, Park SI, Kim H-R, Interleukin-7 Contributes to the Invasiveness of Prostate Cancer Cells by Promoting Epithelial–Mesenchymal Transition, Sci Rep. 9 (2019) 6917. 10.1038/s41598-019-43294-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [122].Balic A, Sørensen MD, Trabulo SM, Sainz B Jr, Cioffi M, Vieira CR, Miranda-Lorenzo I, Hidalgo M, Kleeff J, Erkan M, Heeschen C, Chloroquine Targets Pancreatic Cancer Stem Cells via Inhibition of CXCR4 and Hedgehog Signaling, Molecular Cancer Therapeutics. 13 (2014) 1758–1771. 10.1158/1535-7163.MCT-13-0948. [DOI] [PubMed] [Google Scholar]
- [123].Nagathihalli NS, Castellanos JA, Shi C, Beesetty Y, Reyzer ML, Caprioli R, Chen X, Walsh AJ, Skala MC, Moses HL, Merchant NB, Signal Transducer and Activator of Transcription 3, Mediated Remodeling of the Tumor Microenvironment Results in Enhanced Tumor Drug Delivery in a Mouse Model of Pancreatic Cancer, Gastroenterology. 149 (2015) 1932–1943.e9. 10.1053/j.gastro.2015.07.058. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [124].Mattheolabakis G, Wang R, Rigas B, Mackenzie GG, Phospho-valproic acid inhibits pancreatic cancer growth in mice: Enhanced efficacy by its formulation in poly-(L)-lactic acid-poly(ethylene glycol) nanoparticles, Int J Oncol. 51 (2017) 1035–1044. 10.3892/ijo.2017.4103. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [125].Andersen MN, Etzerodt A, Graversen JH, Holthof LC, Moestrup SK, Hokland M, Møller HJ, STAT3 inhibition specifically in human monocytes and macrophages by CD163-targeted corosolic acid-containing liposomes, Cancer Immunol Immunother. 68 (2019) 489–502. 10.1007/s00262-019-02301-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [126].Wu X, Tang W, Marquez RT, Li K, Highfill CA, He F, Lian J, Lin J, Fuchs JR, Ji M, Li L, Xu L, Overcoming chemo/radio-resistance of pancreatic cancer by inhibiting STAT3 signaling, Oncotarget. 7 (2016) 11708–11723. 10.18632/oncotarget.7336. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [127].Gu D, Schlotman KE, Xie J, Deciphering the role of hedgehog signaling in pancreatic cancer, J Biomed Res. 30 (2016) 353–360. 10.7555/JBR.30.20150107. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [128].Quatannens D, Verhoeven Y, Van Dam P, Lardon F, Prenen H, Roeyen G, Peeters M, Smits ELJ, Van Audenaerde J, Targeting hedgehog signaling in pancreatic ductal adenocarcinoma, Pharmacology & Therapeutics. 236 (2022) 108107. 10.1016/j.pharmthera.2022.108107. [DOI] [PubMed] [Google Scholar]
- [129].Bahra M, Kamphues C, Boas-Knoop S, Lippert S, Esendik U, Schüller U, Hartmann W, Waha A, Neuhaus P, Heppner F, Pietsch T, Koch A, Combination of hedgehog signaling blockage and chemotherapy leads to tumor reduction in pancreatic adenocarcinomas, Pancreas. 41 (2012) 222–229. 10.1097/MPA.0b013e31822896dd. [DOI] [PubMed] [Google Scholar]
- [130].Chen JK, Taipale J, Cooper MK, Beachy PA, Inhibition of Hedgehog signaling by direct binding of cyclopamine to Smoothened, Genes Dev. 16 (2002) 2743–2748. 10.1101/gad.1025302. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [131].Feldmann G, Dhara S, Fendrich V, Bedja D, Beaty R, Mullendore M, Karikari C, Alvarez H, Iacobuzio-Donahue C, Jimeno A, Gabrielson KL, Matsui W, Maitra A, Blockade of Hedgehog Signaling Inhibits Pancreatic Cancer Invasion and Metastases: A New Paradigm for Combination Therapy in Solid Cancers, Cancer Research. 67 (2007) 2187–2196. 10.1158/0008-5472.CAN-06-3281. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [132].Pietrobono S, Stecca B, Targeting the Oncoprotein Smoothened by Small Molecules: Focus on Novel Acylguanidine Derivatives as Potent Smoothened Inhibitors, Cells. 7 (2018) 272. 10.3390/cells7120272. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [133].Stephenson J, Richards DA, Wolpin BM, Becerra C, Hamm JT, Messersmith WA, Devens S, Cushing J, Goddard J, Schmalbach T, Fuchs CS, The safety of IPI-926, a novel hedgehog pathway inhibitor, in combination with gemcitabine in patients (pts) with metastatic pancreatic cancer., JCO. 29 (2011) 4114–4114. 10.1200/jco.2011.29.15_suppl.4114. [DOI] [Google Scholar]
- [134].Wang J, Chan DKW, Sen A, Ma WW, Straubinger RM, Tumor Priming by SMO Inhibition Enhances Antibody Delivery and Efficacy in a Pancreatic Ductal Adenocarcinoma Model, Molecular Cancer Therapeutics. 18 (2019) 2074–2084. 10.1158/1535-7163.MCT-18-0354. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [135].Miyazaki Y, Matsubara S, Ding Q, Tsukasa K, Yoshimitsu M, Kosai K, Takao S, Efficient elimination of pancreatic cancer stem cells by hedgehog/GLI inhibitor GANT61 in combination with mTOR inhibition, Molecular Cancer. 15 (2016) 49. 10.1186/s12943-016-0534-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [136].Han J-B, Sang F, Chang J-J, Hua Y-Q, Shi W-D, Tang L-H, Liu L-M, Arsenic trioxide inhibits viability of pancreatic cancer stem cells in culture and in a xenograft model via binding to SHH-Gli, Onco Targets Ther. 6 (2013) 1129–1138. 10.2147/OTT.S49148. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [137].Wang Y-H, Sui Y-N, Yan K, Wang L-S, Wang F, Zhou J-H, BRD4 promotes pancreatic ductal adenocarcinoma cell proliferation and enhances gemcitabine resistance, Oncol Rep. 33 (2015) 1699–1706. 10.3892/or.2015.3774. [DOI] [PubMed] [Google Scholar]
- [138].Sun F, Zhu Q, Li T, Saeed M, Xu Z, Zhong F, Song R, Huai M, Zheng M, Xie C, Xu L, Yu H, Regulating Glucose Metabolism with Prodrug Nanoparticles for Promoting Photoimmunotherapy of Pancreatic Cancer, Adv Sci (Weinh). 8 (2021) 2002746. 10.1002/advs.202002746. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [139].Codelivery of Small Molecule Hedgehog Inhibitor and miRNA for Treating Pancreatic Cancer | Molecular Pharmaceutics, (n.d.). https://pubs.acs.org/doi/10.1021/mp500847s (accessed July 13, 2023). [DOI] [PMC free article] [PubMed]
- [140].Kumar V, Mondal G, Slavik P, Rachagani S, Batra SK, Mahato RI, Codelivery of Small Molecule Hedgehog Inhibitor and miRNA for Treating Pancreatic Cancer, Mol. Pharmaceutics. 12 (2015) 1289–1298. 10.1021/mp500847s. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [141].Kumar V, Chaudhary AK, Dong Y, Zhong HA, Mondal G, Lin F, Kumar V, Mahato RI, Design, Synthesis and Biological Evaluation of novel Hedgehog Inhibitors for treating Pancreatic Cancer, Sci Rep. 7 (2017) 1665. 10.1038/s41598-017-01942-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [142].Almawash SA, Mondal G, Mahato RI, Coadministration of Polymeric Conjugates of Docetaxel and Cyclopamine Synergistically Inhibits Orthotopic Pancreatic Cancer Growth and Metastasis, Pharm Res. 35 (2018) 17. 10.1007/s11095-017-2303-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [143].You J, Zhao J, Wen X, Wu C, Huang Q, Guan F, Wu R, Liang D, Li C, Chemoradiation therapy using cyclopamine-loaded liquid-lipid nanoparticles and lutetium-177-labeled core-crosslinked polymeric micelles, J Control Release. 202 (2015) 40–48. 10.1016/j.jconrel.2015.01.031. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [144].Zhao J, Wang H, Hsiao C-H, Chow DS-L, Koay EJ, Kang Y, Wen X, Huang Q, Ma Y, Bankson JA, Ullrich SE, Overwijk W, Maitra A, Piwnica-Worms D, Fleming JB, Li C, Simultaneous inhibition of hedgehog signaling and tumor proliferation remodels stroma and enhances pancreatic cancer therapy, Biomaterials. 159 (2018) 215–228. 10.1016/j.biomaterials.2018.01.014. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [145].Jiang T, Zhang B, Zhang L, Wu X, Li H, Shen S, Luo Z, Liu X, Hu Y, Pang Z, Jiang X, Biomimetic nanoparticles delivered hedgehog pathway inhibitor to modify tumour microenvironment and improved chemotherapy for pancreatic carcinoma, Artificial Cells, Nanomedicine, and Biotechnology. 46 (2018) 1088–1101. 10.1080/21691401.2018.1445093. [DOI] [PubMed] [Google Scholar]
- [146].Ray P, Confeld M, Borowicz P, Wang T, Mallik S, Quadir M, PEG-b-poly (carbonate)-derived nanocarrier platform with pH-responsive properties for pancreatic cancer combination therapy, Colloids and Surfaces B: Biointerfaces. 174 (2019) 126–135. 10.1016/j.colsurfb.2018.10.069. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [147].Verma RK, Yu W, Singh SP, Shankar S, Srivastava RK, Anthothecol-encapsulated PLGA nanoparticles inhibit pancreatic cancer stem cell growth by modulating sonic hedgehog pathway, Nanomedicine: Nanotechnology, Biology and Medicine. 11 (2015) 2061–2070. 10.1016/j.nano.2015.07.001. [DOI] [PubMed] [Google Scholar]
- [148].Verma RK, Yu W, Shrivastava A, Shankar S, Srivastava RK, α-Mangostin-encapsulated PLGA nanoparticles inhibit pancreatic carcinogenesis by targeting cancer stem cells in human, and transgenic (KrasG12D, and KrasG12D/tp53R270H) mice, Sci Rep. 6 (2016) 32743. 10.1038/srep32743. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [149].Ingallina C, Costa PM, Ghirga F, Klippstein R, Wang JT, Berardozzi S, Hodgins N, Infante P, Pollard SM, Botta B, Al-Jamal KT, Polymeric glabrescione B nanocapsules for passive targeting of Hedgehog-dependent tumor therapy in vitro, Nanomedicine. 12 (2017) 711–728. 10.2217/nnm-2016-0388. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [150].Tang Y, Zhang Z, Tang Y, Chen X, Zhou J, Identification of potential target genes in pancreatic ductal adenocarcinoma by bioinformatics analysis, Oncol Lett. 16 (2018) 2453–2461. 10.3892/ol.2018.8912. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [151].Modi S, Kir D, Banerjee S, Saluja A, Control of Apoptosis in Treatment and Biology of Pancreatic Cancer, J Cell Biochem. 117 (2016) 279–288. 10.1002/jcb.25284. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [152].Aguilera KY, Le T, Riahi R, Lay AR, Hinz S, Saadat EA, Vashisht AA, Wohlschlegel J, Donahue TR, Radu CG, Dawson DW, Porcupine Inhibition Disrupts Mitochondrial Function and Homeostasis in WNT Ligand–Addicted Pancreatic Cancer, Molecular Cancer Therapeutics. 21 (2022) 936–947. 10.1158/1535-7163.MCT-21-0623. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [153].Zhong Z, Sepramaniam S, Chew XH, Wood K, Lee MA, Madan B, Virshup DM, PORCN inhibition synergizes with PI3K/mTOR inhibition in Wnt-addicted cancers, Oncogene. 38 (2019) 6662–6677. 10.1038/s41388-019-0908-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [154].Gurney A, Axelrod F, Bond CJ, Cain J, Chartier C, Donigan L, Fischer M, Chaudhari A, Ji M, Kapoun AM, Lam A, Lazetic S, Ma S, Mitra S, Park I-K, Pickell K, Sato A, Satyal S, Stroud M, Tran H, Yen W-C, Lewicki J, Hoey T, Wnt pathway inhibition via the targeting of Frizzled receptors results in decreased growth and tumorigenicity of human tumors, Proceedings of the National Academy of Sciences. 109 (2012) 11717–11722. 10.1073/pnas.1120068109. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [155].Dotan E, Cardin DB, Lenz H-J, Messersmith W, O’Neil B, Cohen SJ, Denlinger CS, Shahda S, Astsaturov I, Kapoun AM, Brachmann RK, Uttamsingh S, Stagg RJ, Weekes C, Phase Ib Study of Wnt Inhibitor Ipafricept with Gemcitabine and nab-paclitaxel in Patients with Previously Untreated Stage IV Pancreatic Cancer, Clinical Cancer Research. 26 (2020) 5348–5357. 10.1158/1078-0432.CCR-20-0489. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [156].Ganesh S, Koser ML, Cyr WA, Chopda GR, Tao J, Shui X, Ying B, Chen D, Pandya P, Chipumuro E, Siddiquee Z, Craig K, Lai C, Dudek H, Monga SP, Wang W, Brown BD, Abrams MT, Direct Pharmacological Inhibition of β-Catenin by RNA Interference in Tumors of Diverse Origin, Molecular Cancer Therapeutics. 15 (2016) 2143–2154. 10.1158/1535-7163.MCT-16-0309. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [157].Ghoshal A, Goswami U, Sahoo AK, Chattopadhyay A, Ghosh SS, Targeting Wnt Canonical Signaling by Recombinant sFRP1 Bound Luminescent Au-Nanocluster Embedded Nanoparticles in Cancer Theranostics, ACS Biomater. Sci. Eng. 1 (2015) 1256–1266. 10.1021/acsbiomaterials.5b00305. [DOI] [PubMed] [Google Scholar]
- [158].Liu Q, Zhu H, Tiruthani K, Shen L, Chen F, Gao K, Zhang X, Hou L, Wang D, Liu R, Huang L, Nanoparticle-Mediated Trapping of Wnt Family Member 5A in Tumor Microenvironments Enhances Immunotherapy for B-Raf Proto-Oncogene Mutant Melanoma, ACS Nano. 12 (2018) 1250–1261. 10.1021/acsnano.7b07384. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [159].Feng J, Xu M, Wang J, Zhou S, Liu Y, Liu S, Huang Y, Chen Y, Chen L, Song Q, Gong J, Lu H, Gao X, Chen J, Sequential delivery of nanoformulated α-mangostin and triptolide overcomes permeation obstacles and improves therapeutic effects in pancreatic cancer, Biomaterials. 241 (2020) 119907. 10.1016/j.biomaterials.2020.119907. [DOI] [PubMed] [Google Scholar]
- [160].Daman Z, Faghihi H, Montazeri H, Salinomycin nanoparticles interfere with tumor cell growth and the tumor microenvironment in an orthotopic model of pancreatic cancer, Drug Development and Industrial Pharmacy. 44 (2018) 1434–1442. 10.1080/03639045.2018.1459674. [DOI] [PubMed] [Google Scholar]
- [161].Schlingensiepen K-H, Jaschinski F, Lang SA, Moser C, Geissler EK, Schlitt HJ, Kielmanowicz M, Schneider A, Transforming growth factor-beta 2 gene silencing with trabedersen (AP 12009) in pancreatic cancer, Cancer Science. 102 (2011) 1193–1200. 10.1111/j.1349-7006.2011.01917.x. [DOI] [PubMed] [Google Scholar]
- [162].Melisi D, Ishiyama S, Sclabas GM, Fleming JB, Xia Q, Tortora G, Abbruzzese JL, Chiao PJ, LY2109761, a novel transforming growth factor β receptor type I and type II dual inhibitor, as a therapeutic approach to suppressing pancreatic cancer metastasis, Molecular Cancer Therapeutics. 7 (2008) 829–840. 10.1158/1535-7163.MCT-07-0337. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [163].Melisi D, Garcia-Carbonero R, Macarulla T, Pezet D, Deplanque G, Fuchs M, Trojan J, Oettle H, Kozloff M, Cleverly A, Smith C, Estrem ST, Gueorguieva I, Lahn MMF, Blunt A, Benhadji KA, Tabernero J, Galunisertib plus gemcitabine vs. gemcitabine for first-line treatment of patients with unresectable pancreatic cancer, Br J Cancer. 119 (2018) 1208–1214. 10.1038/s41416-018-0246-z. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [164].Chen X, Jia F, Huang Y, Jin Q, Ji J, Cancer-Associated Fibroblast-Targeted Delivery of Captopril to Overcome Penetration Obstacles for Enhanced Pancreatic Cancer Therapy, ACS Appl. Bio Mater 5 (2022) 3544–3553. 10.1021/acsabm.2c00486. [DOI] [PubMed] [Google Scholar]
- [165].Grell P, Lin C-C, Milella M, Chee CE, Sivakumar S, Peltola KJ, Bostel G, Jankovic D, Altzerinakou M-A, Fabre C, Santoro A, Phase II study of the anti-TGF-β monoclonal antibody (mAb) NIS793 with and without the PD-1 inhibitor spartalizumab in combination with nab-paclitaxel/gemcitabine (NG) versus NG alone in patients (pts) with first-line metastatic pancreatic ductal adenocarcinoma (mPDAC)., JCO. 39 (2021) TPS4173–TPS4173. 10.1200/JCO.2021.39.15_suppl.TPS4173. [DOI] [Google Scholar]
- [166].Wang Y, Gao Z, Du X, Chen S, Zhang W, Wang J, Li H, He X, Cao J, Wang J, Co-inhibition of the TGF-β pathway and the PD-L1 checkpoint by pH-responsive clustered nanoparticles for pancreatic cancer microenvironment regulation and anti-tumor immunotherapy, Biomater. Sci. 8 (2020) 5121–5132. 10.1039/D0BM00916D. [DOI] [PubMed] [Google Scholar]
- [167].Espinoza I, Miele L, Deadly crosstalk: Notch signaling at the intersection of EMT and cancer stem cells, Cancer Letters. 341 (2013) 41–45. 10.1016/j.canlet.2013.08.027. [DOI] [PubMed] [Google Scholar]
- [168].Ranganathan P, Weaver KL, Capobianco AJ, Notch signalling in solid tumours: a little bit of everything but not all the time, Nat Rev Cancer. 11 (2011) 338–351. 10.1038/nrc3035. [DOI] [PubMed] [Google Scholar]
- [169].Mizuma M, Rasheed ZA, Yabuuchi S, Omura N, Campbell NR, de Wilde RF, De Oliveira E, Zhang Q, Puig O, Matsui W, Hidalgo M, Maitra A, Rajeshkumar NV, The gamma secretase inhibitor MRK-003 attenuates pancreatic cancer growth in preclinical models, Mol Cancer Ther. 11 (2012) 1999–2009. 10.1158/1535-7163.MCT-12-0017. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [170].Cook N, Basu B, Smith D-M, Gopinathan A, Evans J, Steward WP, Palmer D, Propper D, Venugopal B, Hategan M, Anthoney DA, Hampson LV, Nebozhyn M, Tuveson D, Farmer-Hall H, Turner H, McLeod R, Halford S, Jodrell D, A phase I trial of the γ-secretase inhibitor MK-0752 in combination with gemcitabine in patients with pancreatic ductal adenocarcinoma, Br J Cancer. 118 (2018) 793–801. 10.1038/bjc.2017.495. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [171].Ristorcelli E, Beraud E, Mathieu S, Lombardo D, Verine A, Essential role of Notch signaling in apoptosis of human pancreatic tumoral cells mediated by exosomal nanoparticles, International Journal of Cancer. 125 (2009) 1016–1026. 10.1002/ijc.24375. [DOI] [PubMed] [Google Scholar]
- [172].Ji Y, Liu X, Li J, Xie X, Huang M, Jiang J, Liao Y-P, Donahue T, Meng H, Use of ratiometrically designed nanocarrier targeting CDK4/6 and autophagy pathways for effective pancreatic cancer treatment, Nat Commun. 11 (2020) 4249. 10.1038/s41467-020-17996-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [173].Franco J, Witkiewicz AK, Knudsen ES, CDK4/6 inhibitors have potent activity in combination with pathway selective therapeutic agents in models of pancreatic cancer, Oncotarget. 5 (2014) 6512–6525. 10.18632/oncotarget.2270. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [174].Weinberg BA, Wang H, Witkiewicz AK, Marshall JL, He AR, Vail P, Knudsen ES, Pishvaian MJ, A Phase I Study of Ribociclib Plus Everolimus in Patients with Metastatic Pancreatic Adenocarcinoma Refractory to Chemotherapy, J Pancreat Cancer. 6 (2020) 45–54. 10.1089/pancan.2020.0005. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [175].Ristorcelli E, Beraud E, Verrando P, Villard C, Lafitte D, Sbarra V, Lombardo D, Verine A, Human tumor nanoparticles induce apoptosis of pancreatic cancer cells, The FASEB Journal. 22 (2008) 3358–3369. 10.1096/fj.07-02855. [DOI] [PubMed] [Google Scholar]
- [176].Kesharwani P, Banerjee S, Padhye S, Sarkar FH, Iyer AK, Hyaluronic Acid Engineered Nanomicelles Loaded with 3,4-Difluorobenzylidene Curcumin for Targeted Killing of CD44+ Stem-Like Pancreatic Cancer Cells, Biomacromolecules. 16 (2015) 3042–3053. 10.1021/acs.biomac.5b00941. [DOI] [PubMed] [Google Scholar]
- [177].Wei X, Senanayake TH, Bohling A, Vinogradov SV, Targeted nanogel conjugate for improved stability and cellular permeability of curcumin: synthesis, pharmacokinetics, and tumor growth inhibition, Mol Pharm. 11 (2014) 3112–3122. 10.1021/mp500290f. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [178].Mondal G, Almawash S, Chaudhary AK, Mahato RI, EGFR-Targeted Cationic Polymeric Mixed Micelles for Codelivery of Gemcitabine and miR-205 for Treating Advanced Pancreatic Cancer, Mol. Pharmaceutics 14 (2017) 3121–3133. 10.1021/acs.molpharmaceut.7b00355. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [179].Mittal A, Chitkara D, Behrman SW, Mahato RI, Efficacy of gemcitabine conjugated and miRNA-205 complexed micelles for treatment of advanced pancreatic cancer, Biomaterials. 35 (2014) 7077–7087. 10.1016/j.biomaterials.2014.04.053. [DOI] [PubMed] [Google Scholar]
- [180].Singh S, Chitkara D, Kumar V, Behrman SW, Mahato RI, miRNA profiling in pancreatic cancer and restoration of chemosensitivity, Cancer Letters. 334 (2013) 211–220. 10.1016/j.canlet.2012.10.008. [DOI] [PubMed] [Google Scholar]
- [181].Chen W, Zhou Y, Zhi X, Ma T, Liu H, Chen BW, Zheng X, Xie S, Zhao B, Feng X, Dang X, Liang T, Delivery of miR-212 by chimeric peptide-condensed supramolecular nanoparticles enhances the sensitivity of pancreatic ductal adenocarcinoma to doxorubicin, Biomaterials. 192 (2019) 590–600. 10.1016/j.biomaterials.2018.11.035. [DOI] [PubMed] [Google Scholar]
- [182].Cao X, Hu Y, Luo S, Wang Y, Gong T, Sun X, Fu Y, Zhang Z, Neutrophil-mimicking therapeutic nanoparticles for targeted chemotherapy of pancreatic carcinoma, Acta Pharmaceutica Sinica B. 9 (2019) 575–589. 10.1016/j.apsb.2018.12.009. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [183].Han X, Li Y, Xu Y, Zhao X, Zhang Y, Yang X, Wang Y, Zhao R, Anderson GJ, Zhao Y, Nie G, Reversal of pancreatic desmoplasia by re-educating stellate cells with a tumour microenvironment-activated nanosystem, Nat Commun. 9 (2018) 3390. 10.1038/s41467-018-05906-x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [184].Emamzadeh M, Desmaële D, Couvreur P, Pasparakis G, Dual controlled delivery of squalenoyl-gemcitabine and paclitaxel using thermo-responsive polymeric micelles for pancreatic cancer, J. Mater. Chem. B 6 (2018) 2230–2239. 10.1039/C7TB02899G. [DOI] [PubMed] [Google Scholar]
- [185].Sun JD, Liu Q, Ahluwalia D, Li W, Meng F, Wang Y, Bhupathi D, Ruprell AS, Hart CP, Efficacy and safety of the hypoxia-activated prodrug TH-302 in combination with gemcitabine and nab-paclitaxel in human tumor xenograft models of pancreatic cancer, Cancer Biol Ther. 16 (2015) 438–449. 10.1080/15384047.2014.1003005. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [186].McDonald PC, Chafe SC, Brown WS, Saberi S, Swayampakula M, Venkateswaran G, Nemirovsky O, Gillespie JA, Karasinska JM, Kalloger SE, Supuran CT, Schaeffer DF, Bashashati A, Shah SP, Topham JT, Yapp DT, Li J, Renouf DJ, Stanger BZ, Dedhar S, Regulation of pH by Carbonic Anhydrase 9 Mediates Survival of Pancreatic Cancer Cells With Activated KRAS in Response to Hypoxia, Gastroenterology. 157 (2019) 823–837. 10.1053/j.gastro.2019.05.004. [DOI] [PubMed] [Google Scholar]
- [187].Serri C, Quagliariello V, Iaffaioli RV, Fusco S, Botti G, Mayol L, Biondi M, Combination therapy for the treatment of pancreatic cancer through hyaluronic acid-decorated nanoparticles loaded with quercetin and gemcitabine: A preliminary in vitro study, Journal of Cellular Physiology. 234 (2019) 4959–4969. 10.1002/jcp.27297. [DOI] [PubMed] [Google Scholar]
- [188].Wang H, Han X, Dong Z, Xu J, Wang J, Liu Z, Hyaluronidase with pH-responsive Dextran Modification as an Adjuvant Nanomedicine for Enhanced Photodynamic-Immunotherapy of Cancer, Advanced Functional Materials. 29 (2019) 1902440. 10.1002/adfm.201902440. [DOI] [Google Scholar]
- [189].Zinger A, Koren L, Adir O, Poley M, Alyan M, Yaari Z, Noor N, Krinsky N, Simon A, Gibori H, Krayem M, Mumblat Y, Kasten S, Ofir S, Fridman E, Milman N, Lübtow MM, Liba L, Shklover J, Shainsky-Roitman J, Binenbaum Y, Hershkovitz D, Gil Z, Dvir T, Luxenhofer R, Satchi-Fainaro R, Schroeder A, Collagenase Nanoparticles Enhance the Penetration of Drugs into Pancreatic Tumors, ACS Nano. 13 (2019) 11008–11021. 10.1021/acsnano.9b02395. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [190].Yin N, Yu H, Zhang X, Lv X, Enhancement of Pancreatic Cancer Therapy Efficacy by Type-1 Matrix Metalloproteinase-Functionalized Nanoparticles for the Selective Delivery of Gemcitabine and Erlotinib, Drug Des Devel Ther. 14 (2020) 4465–4475. 10.2147/DDDT.S270303. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [191].Karandish F, Mamnoon B, Feng L, Haldar MK, Xia L, Gange KN, You S, Choi Y, Sarkar K, Mallik S, Nucleus-Targeted, Echogenic Polymersomes for Delivering a Cancer Stemness Inhibitor to Pancreatic Cancer Cells, Biomacromolecules. 19 (2018) 4122–4132. 10.1021/acs.biomac.8b01133. [DOI] [PubMed] [Google Scholar]
- [192].Ding L, Tang S, Yu A, Wang A, Tang W, Jia H, Oupický D, Nanoemulsion-Assisted siRNA Delivery to Modulate the Nervous Tumor Microenvironment in the Treatment of Pancreatic Cancer, ACS Appl. Mater. Interfaces. 14 (2022) 10015–10029. 10.1021/acsami.1c21997. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [193].Chen Y, Huang Y, Li Q, Luo Z, Zhang Z, Huang H, Sun J, Zhang L, Sun R, Bain DJ, Conway JF, Lu B, Li S, Targeting Xkr8 via nanoparticle-mediated in situ co-delivery of siRNA and chemotherapy drugs for cancer immunochemotherapy, Nat. Nanotechnol 18 (2023) 193–204. 10.1038/s41565-022-01266-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [194].Cun X, Chen J, Li M, He X, Tang X, Guo R, Deng M, Li M, Zhang Z, He Q, Tumor-Associated Fibroblast-Targeted Regulation and Deep Tumor Delivery of Chemotherapeutic Drugs with a Multifunctional Size-Switchable Nanoparticle, ACS Appl. Mater. Interfaces. 11 (2019) 39545–39559. 10.1021/acsami.9b13957. [DOI] [PubMed] [Google Scholar]
- [195].Yu Q, Qiu Y, Li J, Tang X, Wang X, Cun X, Xu S, Liu Y, Li M, Zhang Z, He Q, Targeting cancer-associated fibroblasts by dual-responsive lipid-albumin nanoparticles to enhance drug perfusion for pancreatic tumor therapy, Journal of Controlled Release. 321 (2020) 564–575. 10.1016/j.jconrel.2020.02.040. [DOI] [PubMed] [Google Scholar]
- [196].Valetti S, Maione F, Mura S, Stella B, Desmaële D, Noiray M, Vergnaud J, Vauthier C, Cattel L, Giraudo E, Couvreur P, Peptide-functionalized nanoparticles for selective targeting of pancreatic tumor, Journal of Controlled Release. 192 (2014) 29–39. 10.1016/j.jconrel.2014.06.039. [DOI] [PubMed] [Google Scholar]
- [197].Miao L, Liu Q, Lin CM, Luo C, Wang Y, Liu L, Yin W, Hu S, Kim WY, Huang L, Targeting Tumor-Associated Fibroblasts for Therapeutic Delivery in Desmoplastic Tumors, Cancer Research. 77 (2017) 719–731. 10.1158/0008-5472.CAN-16-0866. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [198].Gao C, Cheng K, Li Y, Gong R, Zhao X, Nie G, Ren H, Injectable Immunotherapeutic Hydrogel Containing RNA-Loaded Lipid Nanoparticles Reshapes Tumor Microenvironment for Pancreatic Cancer Therapy, Nano Lett. 22 (2022) 8801–8809. 10.1021/acs.nanolett.2c01994. [DOI] [PubMed] [Google Scholar]
- [199].Li M, Li M, Yang Y, Liu Y, Xie H, Yu Q, Tian L, Tang X, Ren K, Li J, Zhang Z, He Q, Remodeling tumor immune microenvironment via targeted blockade of PI3K-γ and CSF-1/CSF-1R pathways in tumor associated macrophages for pancreatic cancer therapy, Journal of Controlled Release. 321 (2020) 23–35. 10.1016/j.jconrel.2020.02.011. [DOI] [PubMed] [Google Scholar]
- [200].Xie Y, Hang Y, Wang Y, Sleightholm R, Prajapati DR, Bader J, Yu A, Tang W, Jaramillo L, Li J, Singh RK, Oupický D, Stromal Modulation and Treatment of Metastatic Pancreatic Cancer with Local Intraperitoneal Triple miRNA/siRNA Nanotherapy, ACS Nano. 14 (2020) 255–271. 10.1021/acsnano.9b03978. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [201].Das M, Shen L, Liu Q, Goodwin TJ, Huang L, Nanoparticle Delivery of RIG-I Agonist Enables Effective and Safe Adjuvant Therapy in Pancreatic Cancer, Mol Ther. 27 (2019) 507–517. 10.1016/j.ymthe.2018.11.012. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [202].Mahadevan KK, LeBleu VS, Ramirez EV, Chen Y, Li B, Sockwell AM, Gagea M, Sugimoto H, Sthanam LK, Tampe D, Zeisberg M, Ying H, Jain AK, DePinho RA, Maitra A, McAndrews KM, Kalluri R, Elimination of oncogenic KRAS in genetic mouse models eradicates pancreatic cancer by inducing FAS-dependent apoptosis by CD8+ T cells, Developmental Cell. 58 (2023) 1562–1577.e8. 10.1016/j.devcel.2023.07.025. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [203].Mahadevan KK, McAndrews KM, LeBleu VS, Yang S, Lyu H, Li B, Sockwell AM, Kirtley ML, Morse SJ, Diaz BAM, Kim MP, Feng N, Lopez AM, Guerrero PA, Paradiso F, Sugimoto H, Arian KA, Ying H, Barekatain Y, Sthanam LK, Kelly PJ, Maitra A, Heffernan TP, Kalluri R, KRASG12D inhibition reprograms the microenvironment of early and advanced pancreatic cancer to promote FAS-mediated killing by CD8+ T cells, Cancer Cell. 41 (2023) 1606–1620.e8. 10.1016/j.ccell.2023.07.002. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [204].Zhou X, Liu Y, Hu M, Wang M, Liu X, Huang L, Relaxin gene delivery modulates macrophages to resolve cancer fibrosis and synergizes with immune checkpoint blockade therapy, Science Advances. 7 (2021) eabb6596. 10.1126/sciadv.abb6596. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [205].Zhang Y, Lazarus J, Steele NG, Yan W, Lee H-J, Nwosu ZC, Halbrook CJ, Menjivar RE, Kemp SB, Sirihorachai VR, Velez-Delgado A, Donahue K, Carpenter ES, Brown KL, Irizarry-Negron V, Nevison AC, Vinta A, Anderson MA, Crawford HC, Lyssiotis CA, Frankel TL, Bednar F, Pasca di Magliano M, Regulatory T-cell Depletion Alters the Tumor Microenvironment and Accelerates Pancreatic Carcinogenesis, Cancer Discovery. 10 (2020) 422–439. 10.1158/2159-8290.CD-19-0958. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [206].Sun J, Wan Z, Chen Y, Xu J, Luo Z, Parise RA, Diao D, Ren P, Beumer JH, Lu B, Li S, Triple drugs co-delivered by a small gemcitabine-based carrier for pancreatic cancer immunochemotherapy, Acta Biomaterialia. 106 (2020) 289–300. 10.1016/j.actbio.2020.01.039. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [207].Yang X, Lu Y, Hang J, Zhang J, Zhang T, Huo Y, Liu J, Lai S, Luo D, Wang L, Hua R, Lin Y, Lactate-Modulated Immunosuppression of Myeloid-Derived Suppressor Cells Contributes to the Radioresistance of Pancreatic Cancer, Cancer Immunology Research. 8 (2020) 1440–1451. 10.1158/2326-6066.CIR-20-0111. [DOI] [PubMed] [Google Scholar]
- [208].Zhu Y, Knolhoff BL, Meyer MA, Nywening TM, West BL, Luo J, Wang-Gillam A, Goedegebuure SP, Linehan DC, DeNardo DG, CSF1/CSF1R Blockade Reprograms Tumor-Infiltrating Macrophages and Improves Response to T-cell Checkpoint Immunotherapy in Pancreatic Cancer Models, Cancer Research. 74 (2014) 5057–5069. 10.1158/0008-5472.CAN-13-3723. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [209].Sun J, Wan Z, Xu J, Luo Z, Ren P, Zhang B, Diao D, Huang Y, Li S, Tumor size-dependent abscopal effect of polydopamine-coated all-in-one nanoparticles for immunochemo-photothermal therapy of early- and late-stage metastatic cancer, Biomaterials. 269 (2021) 120629. 10.1016/j.biomaterials.2020.120629. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [210].Mekapogu AR, Pothula SP, Pirola RC, Wilson JS, Apte MV, Multifunctional role of pancreatic stellate cells in pancreatic cancer, Annals of Pancreatic Cancer. 2 (2019). 10.21037/apc.2019.05.02. [DOI] [Google Scholar]
- [211].Matsumoto S, Nakata K, Sagara A, Guan W, Ikenaga N, Ohuchida K, Nakamura M, Efficient pre-treatment for pancreatic cancer using chloroquine-loaded nanoparticles targeting pancreatic stellate cells, Oncology Letters. 22 (2021) 1–8. 10.3892/ol.2021.12894. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [212].Kozono S, Ohuchida K, Eguchi D, Ikenaga N, Fujiwara K, Cui L, Mizumoto K, Tanaka M, Pirfenidone Inhibits Pancreatic Cancer Desmoplasia by Regulating Stellate Cells, Cancer Research. 73 (2013) 2345–2356. 10.1158/0008-5472.CAN-12-3180. [DOI] [PubMed] [Google Scholar]
- [213].Kajiwara I, Sano M, Ichimaru Y, Oshima Y, Kitajima O, Hao H, Masamune A, Kim J, Ishii Y, Ijichi H, Suzuki T, Duloxetine improves cancer-associated pain in a mouse model of pancreatic cancer through stimulation of noradrenaline pathway and its antitumor effects, PAIN. 161 (2020) 2909. 10.1097/j.pain.0000000000001997. [DOI] [PubMed] [Google Scholar]
- [214].Sun L, Chen K, Jiang Z, Chen X, Ma J, Ma Q, Duan W, Indometacin inhibits the proliferation and activation of human pancreatic stellate cells through the downregulation of COX-2, Oncology Reports. 39 (2018) 2243–2251. 10.3892/or.2018.6321. [DOI] [PubMed] [Google Scholar]
- [215].Chronopoulos A, Robinson B, Sarper M, Cortes E, Auernheimer V, Lachowski D, Attwood S, García R, Ghassemi S, Fabry B, del Río Hernández A, ATRA mechanically reprograms pancreatic stellate cells to suppress matrix remodelling and inhibit cancer cell invasion, Nat Commun. 7 (2016) 12630. 10.1038/ncomms12630. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [216].Han H, Hou Y, Chen X, Zhang P, Kang M, Jin Q, Ji J, Gao M, Metformin-Induced Stromal Depletion to Enhance the Penetration of Gemcitabine-Loaded Magnetic Nanoparticles for Pancreatic Cancer Targeted Therapy, J. Am. Chem. Soc. 142 (2020) 4944–4954. 10.1021/jacs.0c00650. [DOI] [PubMed] [Google Scholar]
- [217].Farrell S, Nesbitt H, Mairs L, Nomikou N, Callan B, Callan JF, McHale AP, O-P03 A composite polymeric nanoparticle as a sensitiser for sonodynamic therapy (SDT)-based treatment of pancreatic cancer, British Journal of Surgery. 108 (2021) znab429.044. 10.1093/bjs/znab429.044. [DOI] [Google Scholar]
- [218].Schnittert J, Kuninty PR, Bystry TF, Brock R, Storm G, Prakash J, Anti-microRNA targeting using peptide-based nanocomplexes to inhibit differentiation of human pancreatic stellate cells, Nanomedicine. 12 (2017) 1369–1384. 10.2217/nnm-2017-0054. [DOI] [PubMed] [Google Scholar]