Abstract
The delivery of chemotherapeutics to solid tumors using smart drug delivery systems (SDDSs) takes advantage of the unique physiology of tumors (i.e., disordered structure, leaky vasculature, abnormal extracellular matrix (ECM), and limited lymphatic drainage) to deliver anticancer drugs with reduced systemic side effects. Liposomes are the most promising of such SDDSs and have been well investigated for cancer therapy. To improve the specificity, bioavailability, and anticancer efficacy of liposomes at the diseased sites, other strategies such as targeting ligands and stimulus-sensitive liposomes have been developed. This review highlights relevant surface functionalization techniques and stimuli-mediated drug release for enhanced delivery of anticancer agents at tumor sites, with a special focus on dual functionalization and design of multistimuli responsive liposomes.
Keywords: cancer, nanocarrier, targeted delivery, liposomes, active targeting, stimulus
Introduction
Cancer is the second leading cause of noncommunicable disease (NCD) deaths globally, causing approximately 9 million deaths annually.1 According to the American Cancer Society (ACS), in the year 2021, an estimated 1.9 million new cancer cases are expected to be diagnosed and over 600 000 deaths will be caused by the disease in the United States alone.2 The principal treatment strategies against cancer include surgery, chemotherapy, radiation therapy, and hormone therapy. Surgery can be used to determine whether a certain mass is cancerous, determine the extent of cancer, excise cancerous masses, and reconstruct tissues and organs affected by cancer.
Radiation therapy is another common technique used to treat nonmetastatic malignancies. Radiotherapy involves destroying cancer cells using high-energy particles or waves (e.g., X-rays, γ rays). In contrast to surgery and radiation, chemotherapy is used to treat cancer throughout the whole body, making it an invaluable tool for the treatment of disseminated or metastatic cancer. On the other hand, hormone therapy can only be used in the treatment of hormone-sensitive types of cancer and aims to stop hormone synthesis and prevent hormone-positive effects on cancer cells.3−5
The aforementioned treatments are often accompanied by adverse side effects, such as fatigue, hair loss, infections, pain, nausea, mucositis, and vomiting, that can significantly reduce the quality of life of cancer patients. In recent years, a wide range of drug delivery systems (DDSs) have been developed to improve cancer therapies.3,6,7 DDSs are nanoplatforms capable of delivering therapeutic agents to the diseased area and releasing their contents in response to an internal (e.g., temperature, pH, enzymes) or external trigger (e.g., temperature, light, mechanical waves, electric and magnetic fields). A variety of DDSs have been developed, including micelles, dendrimers, liposomes, solid nanoparticles, carbon nanotubes (CNTs), silica nanoparticles, and quantum dots (QDs).8,9 Liposomes are among the most successful DDSs and have found numerous applications in targeted drug delivery. In this review, we will focus on recent developments pertaining to the use of liposomes in cancer treatment, particularly on the use of active targeting mechanisms and stimuli-responsive targeting.
Passive and Active Targeting
Before nanocarriers reach their targeted sites, they need to overcome several biological barriers created by the host immune system, in addition to the abnormal tumor physiology, which includes defective vasculature, abnormal ECM, and high interstitial fluid pressure. Therefore, the physical and chemical properties of nanoparticles (NPs) are of particular importance in drug delivery applications. The size and shape of NPs are important in determining the NPs’ circulation time and targeting within the body.10 Particles with diameters greater than 150 nm are detected by organs of the reticuloendothelial system (RES), while particles with a diameter smaller than 100 nm will remain within the fenestrae of the endothelial lining of blood vessels, hence reducing the possibility of being recognized and phagocytized. As for shape, studies have reported that spherically shaped particles are internalized more easily than NPs of other shapes.3,10 Moreover, hydrophobicity, surface charge, and surface ligands influence the NPs’ behavior in vivo and produce significant changes in their performance.
Tumor vasculature is often defective and leaky, with wide fenestrations between cells and limited lymphatic drainage. These factors allow the accumulation of NPs within the tumor interstitium, a phenomenon known as the enhanced permeability and retention (EPR) effect.11−13 Passive targeting uses the unique pathophysiology of tumor vessels as well as the EPR effect to enable the accumulation of nanocarriers at tumor sites. Active targeting can significantly increase the amount of drug delivered to the tumor site compared to passively targeted NPs. It entails specific interactions between the targeted cells and the drug carrier through receptor–ligand interactions. Some receptors are often overexpressed on tumor cells; therefore, surface-modified nanocarriers displaying complementary ligands will recognize and bind to these receptors (refer to Figure 1). The formed complex is then internalized through receptor-mediated endocytosis, thereby enhancing cellular uptake and facilitating drug release inside the cell.3,11,12
Figure 1.
Passive and active targeting of tumors.
Liposomes
The use of liposomes in targeted drug delivery has been thoroughly investigated. Liposomes were first developed by Alec Bangham in the early 1960s14 when he noticed that phospholipids naturally form vesicles when dispersed in an aqueous medium. Ever since their discovery, liposomes have been used in numerous applications. Liposomes are concentric spherical vesicles consisting of one or more lipid bilayers surrounding an aqueous core. Within a bilayer, the hydrophilic heads of the phospholipids are directed outward (to the aqueous phase), while the hydrophobic tails are directed into the membrane interior. The amphipathic nature of liposomes enables them to entrap both hydrophilic and hydrophobic drugs within the aqueous interior and the membrane, respectively. Liposomes offer several advantages over other nanocarrier systems; these include biocompatibility, biodegradability, nonimmunogenicity, enhancing drug solubility, sustaining drug release over time, reducing the toxic effect of drugs, increasing drug concentration at the target site, aiding in overcoming multidrug resistance (MDR), as well as improving the therapeutic index of the entrapped drug.15,16
Liposomes can be categorized according to structure, composition, and preparation method. Based on structure, liposomes are divided into unilamellar, multilamellar, and multivesicular. In terms of composition, liposomes can be classified into conventional, fusogenic, long circulatory, pH-sensitive, ionic, magnetic, heat-sensitive, and immunoliposomes (refer to Figure 2).16 The choice of liposomal preparation method depends on the membrane components’ physicochemical properties, the payload, and the dispersing medium.17,18 Techniques for liposome preparation are divided into mechanical dispersion methods (e.g., lipid film hydration, sonication, microemulsification, French pressure cell, membrane extrusion, and freeze–thawing), solvent dispersion methods (e.g., ethanol/ether injection, double emulsion, and reverse-phase evaporation) and detergent solubilization (e.g., dialysis, column chromatography, and dilution).16,18
Figure 2.
Classification of liposomes based on size, structure, and preparation method.
Liposome Surface Functionalization
Functionalization of Liposomes Using Polyethylene Glycol (PEG)
Drug delivery applications necessitate extended circulation times, which means that liposomes must evade detection and clearance by organs of the RES. This desired invisibility can be imparted onto liposomes by decorating their surfaces with molecular groups or polymers that suppress opsonization by plasma proteins; these liposomes are known as “stealth liposomes.” The most commonly used polymeric substance is polyethylene glycol (PEG).3,19
PEG is a highly biocompatible, nonimmunogenic synthetic, linear polyether diol characterized by ease of synthesis, high flexibility, and aqueous/organic solubility. The presence of PEG on the surface of liposomes helps extend their blood circulation time, reduce their uptake by the RES, enhance the stability of the formulations, and improve their distribution in the targeted area.20,21 However, recent research has brought to light some drawbacks of functionalizing nanocarriers with PEG, particularly the potential immunogenicity of the PEG-coating manifesting as the accelerated blood clearance (ABC) phenomenon. The ABC phenomenon is an immunogenic response involving the rapid clearance of the second dose of PEGylated nanocarriers when administered after a certain time interval following the first dose due to increased accumulation in the liver.22,23 Although the ABC phenomenon poses a significant issue with the repeated administration of non- or moderately cytotoxic agents or immunostimulatory agents, it does not pose a problem for PEGylated nanocarriers used in cancer therapy because of the higher lipid content of nanocarriers encapsulating chemotherapeutic agents (e.g., doxorubicin, oxaliplatin, mitoxantrone, topotecan).22−25
Functionalization of Liposomes Using Targeting Ligands
Active targeting was defined earlier as the modification of NPs with targeting moieties, enabling them to recognize and bind to target cells through ligand–receptor interactions. Active targeting is particularly beneficial in cancer therapy because specific ligand–receptor interactions reduce nonspecific interactions that may increase normal tissue toxicity. Actively targeted liposomal systems are made by grafting moieties, such as peptides, proteins, monoclonal antibodies, aptamers, carbohydrates, and other small molecules, onto the surface of liposomes. The targeting moiety can be either integrated directly into the lipid membrane or attached to the distal end of the polymeric coating, i.e., PEG.11,19,26
Folic Acid
Folic acid (FA) is a low molecular-weight vitamin used by eukaryotic cells for single-carbon metabolism and the synthesis of nucleotide bases. The cellular uptake of FA can occur through either the reduced folate carrier (RFC) or the folate receptor (FR). The RFC uses membrane carrier proteins to transport folate across the cell membrane. On the other hand, the FR is a glycoprotein receptor that mediates the endocytosis of folate. The RFC is distributed all over and functions in the uptake of dietary folate. In contrast, the FR has four known isoforms (FR-α, FR-β, FR-γ, and FR-δ) that are upregulated on activated macrophages and cancer cells.27−29 FR-α is overexpressed in ovarian carcinomas and other epithelial cancers, FR-β is overexpressed in myeloid leukemia, FR-δ is expressed in regulatory T cells, while FR-γ is secreted by the lymphoid cells.29
Several folate-conjugated liposomal systems have been reported in literature. Moghimipour et al.30 prepared 5-fluorouracil (5FU)-loaded-FA liposomes. In vitro studies were performed using colon carcinoma (CT26) cells, while the antitumor activity and tissue toxicity were studied in vivo. FA-liposomes showed higher cellular uptake and tumor inhibition than the free drug on cancer cells (89 mm3 and 210 mm3 tumor volumes, respectively). Zhu et al.31 compared the anticancer activity of docetaxel (DTX)-loaded FA-liposomes (LPs-DTX-FA) to that of co-spray-dried LPs-DTX-FA. Although the co-spray-dried liposomes showed higher cellular uptake and cytotoxicity than LPs-DTX-FA, they exhibited less specific tumor targeting. The in vivo study results showed a 45-fold higher concentration of DTX in the lungs of Sprague–Dawley rats when tracheal administration was used compared with intravenous administration. The findings of this study showed that co-spray-drying is able to change the properties of the NPs and that tracheal administration of the dried liposomal formulation gave higher drug exposure at the tumor site.
In another study, Wang et al.32 synthesized FA-modified curcumin (CUR)-loaded liposomes and evaluated their antitumor activity. The characterization of the developed liposomes included particle size, transmission electron microscopy (TEM), and zeta potential. In vitro studies using cervical cancer (HeLa cells) were used to determine percent drug entrapment efficiency (%EE), drug-loading (%DL) capacity, growth inhibition, cellular uptake, and release properties. The pharmacodynamics were studied in vivo using Balb/c mice. The results of the characterization tests showed that the spherical liposomes had an average diameter of approximately 110.3 nm, revealing that the liposomes are within the size range to take advantage of the EPR effect (10–200 nm).33 The zeta potential was just above −15 mV. The %EE and %DL of developed liposomes were 87.6% and 7.9%, respectively. Furthermore, the cellular uptake of the liposomes was enhanced 10-fold when free CUR was compared to FA-LPs/CUR-treated HeLa cells. In the in vivo studies, the cytoplasms of tumor cells treated with coumarin-6 labeled FA-modified CUR-LPs showed strong green fluorescence. Additionally, a considerable reduction of the tumor volumes was observed.
Transferrin (Tf)
Iron is an essential cofactor of proteins involved in numerous cellular processes, including oxygen transport, metabolism, production of enzymes, hematopoiesis, and DNA synthesis. Mammals obtain the iron needed to maintain bodily functions from their diets. Transferrin (Tf) is part of a family of proteins that bind to iron and deliver it into cells via interactions with its receptor. Tf is a double-lobed serum glycoprotein secreted by the liver.34 Iron-free Tf, also known as apo-Tf, can bind to two iron molecules forming diferric or holo-Tf, which in turn binds to transferrin receptors (TfRs). Once bound to the receptor, the complex is internalized into the endosome through receptor-mediated endocytosis, where the acidic environment (pH ∼ 5.5) causes structural rearrangements of the Tf-TfR complex inducing iron release. Following iron release, the Tf-TfR complex is recycled to the cell surface where the return to physiological pH (pH ∼ 7.4) will dissociate the complex and release Tf for reuse.35
The TfR family includes TfR1 (also known as CD71) and TfR2 (also known as CD77). TfR1 is a high affinity, ubiquitously expressed receptor in most normal human tissues, while TfR2 is largely restricted to hepatocytes. However, TfR1 expression is much higher on malignant cells than on healthy cells, and its expression can be correlated with tumor stage and cancer progression. The overexpression of TfR1 on cancer cells can be attributed to the rapid proliferation of cancer cells, which entails a higher iron demand for DNA synthesis and cell cycle progression. The overexpression of the TfR on malignant cells and the necessity for iron in cancer proliferation make TfRs attractive targets for cancer therapy.34−36
Several Tf-functionalized liposomal systems have been developed for the delivery of chemotherapeutics to tumor cells overexpressing the TfR. Glioblastomas (GBMs) are highly aggressive and infiltrative brain tumors with a therapy-insensitive environment, resistant to aggressive treatments that may include surgical removal, radiation, and chemotherapy. The main hurdle to their successful treatment using chemotherapy is the tight junctions of endothelial cells in the brain and the low permeability of the blood-brain barrier (BBB), which limits the delivery of drugs to the brain. This demands high doses of chemotherapeutics to be administered in order to reach therapeutic concentrations in the brain, which may lead to systemic toxicity.
Since TfRs are overexpressed in GBMs, Jhaveri et al.37 exploited the active targeting abilities of Tf-modified Resveratrol (Res)-encapsulating liposomes (called Tf-Res-Ls) to treat GBMs. Res-liposomes were found to be stable, with good %DL and prolonged drug release in vitro. Flow cytometry and confocal microscopy were used to study targeted and nontargeted liposomes’ internalization into human malignant glioma (U-87 MG) cells. The Tf-Res-Ls exhibited higher apoptosis levels in GBM cells compared to free Res or Res-L. Tumor growth inhibition and survival rate were measured in vivo. At the end of the study, the research group observed a 50% reduction in tumor volumes when comparing free Res with Tf-Res-L treated tumors. For the survival analysis, the survival end point was defined as the time taken for the tumor volume to reach 1000 mm3. After 25 days of initiating the treatment, approximately 60% of the animals in the Tf-Res-L group had not reached the cutoff volume, whereas only 20% of the animals in the free Res and Res-L treatment groups had yet to reach that stage. Sakpakdeejaroen et al.38 investigated the therapeutic potential of plumbagin entrapped in Tf-conjugated liposomes. In vitro study results showed that the encapsulation of plumbagin in Tf-bearing liposomes increased plumbagin uptake by cancer cells in skin melanoma, epidermoid carcinoma, and human glioblastoma multiforme cell lines compared with that observed with the unencapsulated drug solution.
Moghimipour et al.39 investigated the use of Tf-targeted liposomal 5FU to treat colon cancer. The in vitro cytotoxicity of the synthesized liposomes was investigated using the MTT assay on colorectal adenocarcinoma (HT-29) cells in vitro, while fibroblasts were used as control cells. The cytotoxicity mechanism of Tf-liposomes was assessed through the production of reactive oxygen species (ROS), release of cytochrome c, and mitochondrial membrane potential. The characterization tests showed that the average size of the targeted liposomes was slightly above 100 nm and hence they were within the size range to take advantage of the EPR effect and could be useful as a drug carrier system, and that the encapsulation efficiency was ∼59%. The findings of the MTT assay revealed that Tf-targeted liposomes had higher cytotoxic activity in comparison to free 5FU and nontargeted liposomes. Also, lower mitochondrial membrane potential and release of cytochrome c indicated that Tf-liposomes killed cancer cells through the activation of mitochondrial apoptosis pathways.
Antibodies
Monoclonal antibodies (mAbs) and their fragments (fragment antigen-binding (Fab)) are target-recognizing proteins commonly used in cancer drug delivery applications.40,41 Moreover, single-chain variable (scFv) fragments are fusion proteins composed of a variable region of the heavy and light chains of an antibody connected by a peptide linker.42 The modification of liposomes with mAbs and Fabs to generate immunoliposomes has been used for targeted delivery in cancer therapy.
Gabbia et al.43 compared the in vivo liver toxicity of stealth immunoliposomes (SIL) and superstealth immunoliposomes (SSIL2), loaded with doxorubicin (DOX). Standard histological analyses showed that SIL-treated rats exhibited numerous granulomas, whereas the livers of SSIL2-treated animals exhibited only a few isolated granulomas. Khayrani et al.44 assessed the therapeutic efficacy of glycosylated paclitaxel (gPTX)-loaded liposomes functionalized with anti-CD44 antibody (gPTX-IL). The in vitro cytotoxicity of gPTX-IL was tested in SK-OV-3 and OVK18 ovarian cancer cell lines. Antitumor activity in vivo was evaluated by monitoring loss of body weight and H&E staining of the liver, kidney, and spleen; accordingly, gPTX-IL exhibited the most effective antitumor activity.
Zheng et al.45 synthesized ScFv modified liposomes with an additional C-terminal cysteine residue to target fibroblast growth factor receptor 3 (FGFR3). RT112 and T24 bladder cancer cell lines were chosen as high FGFR3-expressing and low FGFR3-expressing cell lines, respectively. The lipophilic Dio fluorescent dye was used to label both control and targeted liposomes. Immunoliposome-treated RT112 cells showed more green fluorescence compared to the cells treated with nontargeted liposomes, indicating that immunoliposomes are better at delivering Dio into high FGFR3-expressing RT112 cells.
Peptides
Peptides are short chains of amino acids connected by peptide bonds and are typically distinguished from proteins by their shorter length.46 Although mAbs have shown potential as tumor-targeting agents; they are limited by their large molecular size, high affinity to antigens leading to poor tumor penetration, and liver and bone marrow toxicity due to nonspecific antibody uptake.47 Peptides can overcome these limitations because they are smaller and easier to produce and manipulate. Furthermore, peptides have a moderate affinity to antigens, resulting in better tumor penetration compared to antibodies.48−50
Zhang et al.51 synthesized β3 integrin specific ligand (B3int)-modified liposomes encapsulating DOX (B3int-LS-DOX). In vitro cellular uptake studies were conducted using prostate cancer (PC-3 and DU-145) cell lines. The developed liposome displayed higher uptake in PC-3 cells than in DU-145 cells, generating a 3-fold increase in intracellular DOX in the former. Furthermore, in cell viability assays, B3int-LS-DOX exhibited significant inhibitory effects in PC-3 tumor cells. In another study, Tang et al.52 synthesized gemcitabine (GEM)-loaded RGD modified liposomes (RGD-GEM-LPs). RGD peptides are known to bind preferentially to the αvβ3 integrin. The in vitro release studies showed that the mechanism of GEM release from both targeted and nontargeted liposomes involved distinct burst release for 30 min after administration. Noninvasive fluorescence imaging was used to monitor the tumor-targeting efficiency of RGD-GEM-LPs in mice bearing SKOV3 ovarian cancer xenografts. The imaging results showed that the uptake of DiD delivered to tumors by RGD-GEM-LPs increased gradually compared to healthy tissues following injection, which suggested that these liposomes were more likely to accumulate in tumors than in normal tissues. The cellular uptake studies showed that RGD-GEM-LPs uptake was approximately 2.5-fold higher than that of GEM-LPs, which was attributed to the targeting capacity of the αvβ3 integrin.
Ji et al.53 synthesized a matrix metalloproteinase-2 (MMP-2) responsive peptide (SDK(C18)SGPLG-IAGQSK(C18)DS)-hybrid liposome loaded with pirfenidone (MRPL-PFD) to treat pancreatic cancer. Pancreatic tumor development involves the proliferation of pancreatic stellate cells (PSCs) and secretion of ECM in the tumor stroma, which reduces drug delivery and penetration in tumor tissue. Therefore, decreasing ECM secretions through the regulation of PSCs has the ability to enhance the penetration of therapeutic drugs, thus enhancing their therapeutic efficacy. The developed MRPL-PFDs were explicitly designed to release PFD at the pancreatic tumor site, leading to the downregulation of the ECM by the PSCs and hence enabling the penetration of GEM into the tumor tissue.
Carbohydrates
Glycosylation refers to the reaction in which a carbohydrate is attached to a functional group of another molecule. Abnormal glycosylation and carbohydrate alterations on cell membranes are associated with various cancer processes, including tumorigenesis, malignant transformation, and tumor metastasis.54 To be recognized and taken up by cells, carbohydrate-decorated liposomes require suitable receptors. Lectins are a class of carbohydrate-binding proteins that are highly specific for certain sugar groups.55 Lectins are overexpressed on several cell surfaces; hence, glycosylated vehicles can be recognized and endocytosed by lectin receptors.56 Several liposome preparations displaying various carbohydrates on the outer membrane surface of liposomes have been reported in literature.
Minnelli et al.57 investigated the therapeutic effect of mannose-6-phosphate (M6P) liposomes in breast cancer cells (MCF7) and human dermal fibroblast cells (HDF). The liposomes were loaded with the model drug calcein and N-hexanoyl-d-erythro-sphingosine (C6Cer). DLS measurements, spectrophotometric turbidity measurements, and flow cytometry analysis showed increased uptake of M6P liposomes by the MCF7 cells compared to HDF cells. Tian et al.58 reported a dual-functional hyaluronic acid (HA) modified-PTX loaded liposome system targeting both the CD44 receptor and mitochondria to reduce the drug resistance of cancer cells and trigger apoptosis. The in vivo study results showed that the uptake of HA liposomes increased by approximately 5-fold in A549/T cells compared with uncoated liposomes.
Dual Targeting
A recent trend in the surface functionalization of liposomes involves the decoration of the liposomal surface with two ligands. Dual-targeted liposomes offer several advantages, such as targeting two or more receptors, subsequently delivering more drugs to the cells. Another advantage is enabling the loaded drug to exert therapeutic effects in multiple ways. Dual targeting could also be a strategy to reduce normal tissue toxicity.59,60 Several research groups have developed dual-ligand liposome formulations. For example, Ke et al.61 synthesized aspartate (Asp8) and folate modified DOX-loaded liposomes (A/F-LS). Characterization tests showed that the %EE of DOX for all liposomes was more than 90% and the surface modification did not affect the ultimate %EE. The in vitro assays and in vivo distribution imaging indicated that A/F-LS has a strong bond targeting effect. A/F-LS showed high cellular uptake by FR-rich tumor cells, which resulted in the high cytotoxicity of the encapsulated DOX. In addition, pharmacokinetics and tissue distribution studies suggested that the developed liposomes had prolonged blood circulation times and favored DOX accumulation in the tumor. Lakkadwala et al.62 obtained similar results in another study involving dual-targeting liposomes. These liposomes were functionalized with Tf and a cell-penetrating peptide (CPP). The in vitro and in vivo studies results showed that Tf-CPP liposomes resulted in more than a 10-fold increase in DOX accumulation and an approximately 3-fold increase in erlotinib accumulation in mice brains, respectively.
Pu et al.63 designed and developed two types of dual-functionalized triple-negative breast cancer targeting (TNBC) liposomes. The developed liposomes were modified with a fructose and RGD peptide (Fru-RGD-Lip) to actively recognize the fructose transporter GLUT5 and the integrin αvβ3. The results indicated that the PXT-loaded Fru-RGD-Lip achieved the greatest growth inhibition of MDA-MB-231 and 4T1 cells. Table 1 provides further examples of recent studies focusing on dual functionalization.
Table 1. Summary of Recent Studies Focusing on Dual-Targeted Liposomesa.
| moiety | payload | cancer cell line | animal model | main findings | ref |
|---|---|---|---|---|---|
| Asp8 and folate | DOX | breast cancer (MDA-MB-231) cells | (1) optimal density of Asp8 and folate on the liposomes was chosen to be 15% and 10% (molar ratio), respectively | (61) | |
| (2) DOX-A/F-LS treatment prolonged median survival time by 1.7, 1.4, 1.2, and 1.3-times compared to the treatment groups of physiological saline, free DOX, DOX-A-LS, and DOX-F-LS, respectively | |||||
| Tf and Pen | DOX and erlotinib | glioblastoma (U87) cells | male/female nude mice | (1) Tf-Pen liposomes demonstrated ∼12 and 3.3-fold increase in DOX and erlotinib accumulation in mice brains | (64) |
| (2) Tf-Pen liposomes achieved around 90% tumor regression with an increase in the median survival time (36 days) and no toxicity | |||||
| Tf, TAT, and QLPVM | DOX and erlotinib | glioblastoma (U87), brain endothelial (bEnd.3) and glial cells | male/female nude mice | (1) biodistribution profile of Tf-CPP liposomes showed more than 10- and 2.7-fold increase in DOX and erlotinib accumulation in mice brains | (62) |
| Fru and RGD | PXT | breast cancer (MDA-MB-231 and 4T1) cells | Balb/C mice | (1) cellular uptake of Fru-RGD-Lip by MDA-MB-231 and 4T1 cells was 3.19- and 3.23-fold more than that of uncoated liposomes | (63) |
| (2) The uptake of Fru+RGD-Lip was slightly lower, giving a 2.81- and 2.90-fold increase than that of Lip in two cell lines, respectively | |||||
| Tf and R8 | DOX | ovarian carcinoma (A2780) cells | immunodeficient female Ncr NU/NU nude mice | (1) dual DOX-L showed approximately 30% and 10% more cell death than R8 DOX-L | (65) |
| (2) At the end of the study, the tumor volumes were 900.3 ± 60.0 mm3 for control tumors, 848.6 ± 218.2 mm3 for Free DOX, and 124.9 ± 33.69 mm3 for Dual DOX-L | |||||
| T7 and DA7R | DOX and VCR | human umbilical vein endothelial cells (HUVECs), glioma | female ICR mice | (1) codelivery of drugs (DOX+VCR) by the T7/ DA7R-LS increased the cytotoxicity, with an IC50 of 3.54 μg/mL, compared to 4.12, 4.09, and 4.6 μg/mL for T7-LS, DA7R-LS, and N-L | (66) |
| C6 cells and mouse brain endothelial bEnd.3 | (2) % survival of C6 cells after addition of free DOX+free VCR, N-LS, DA7R-LS, T7-LS, and T7/D A7R-LS, was 97.88 ± 2.53, 92.86 ± 3.33, 91.14 ± 1.74, 39.64 ± 2.94, and 40.05 ± 2.12%, respectively | ||||
| angiopep-2 and A15 aptamers | survivin siRNA and PTX | human glioblastoma astrocytoma (U251) cells | male BALB/c nude mice | (1) DP-CLPs–PTX–siRNA nanocomplex induced selective apoptosis of CD133+ glioma stem cells | (67) |
| (2) The liposomes markedly inhibited tumorigenesis, and improved survival rates. | |||||
| Glu and Vc | PTX | glioma (C6) cells | Kunming mice | (1) cellular uptake of CFPE-labeled Glu-Vc-Lip on GLUT1- and SVCT2-overexpressed C6 cells was 4.79-, 1.95-, 4.00- and 1.53-fold higher than that of Lip, Glu-Lip, Vc-Lip and Glu + Vc-Lip | (68) |
| (2) in vivo uptake efficiency was enhanced by 7.53-fold to that of free PTX | |||||
| Glu6 and RGD | PTX | breast cancer (MDA-MB-231) cells | female Balb/c nu mice | (1) in vivo targeting showed that PTX-Glu6-RGD-Lip favored accumulation in the metastatic bones | (69) |
| Glu6 and FA | PTX | breast cancer (MDA-MB-231 and MCF10A) cells | female Balb/c nu mice | (1) (AUC0–t) increased by about 1.66-time for PTX-Glu6-FA-Lip compared to free PTX | (70) |
| (1) following the injection of PTX-Glu6-FA-Lip, PTX was nearly 10 times higher than with PTX injected, 2–6 times higher than with PTX-Lip injected, and 1–3 times higher than with PTX-Glu6-Lip, PTX-FA-Lip and PTX-Glu6+FA-Lip | |||||
| HA and FA | siBcl-2 | cervical carcinoma (HeLa) cells | female nude mice | (1) fluorescence intensity of HA/FA-Lip/siRNAFAM was 2.1 times higher than Lip/siRNAFAM group and 1.8 times that of HA-Lip/siRNAFAM | (71) |
| (2) HA-FA-Lip/siBcl-2 group showed a good silencing effect and low cytotoxicity when the siRNA concentration was set to 100 nM |
Abbreviations: Asp8, aspartate; DOX, doxorubicin; Tf, transferrin; Pen, penetratin; Fru, fructose; PXT, paclitaxel; R8, octaarginine; VCR, vincristine; Glu, glucose; Vc, vitamin C; Glu6, glutamic oligopeptide; HA, hyaluronic acid; FA, folic acid.
Stimuli-Responsive Liposomes
The tumor microenvironment has certain defining characteristics (e.g., lower pH, higher temperature, and enzymatic level) that can be exploited to enhance liposomal release at target sites. Stimuli-responsive liposomes are designed to destabilize and release their payload upon exposure to a specific stimulus. Stimuli are broadly divided into internal and external triggers. Internal triggers include pH, temperature, redox, and enzyme level, whereas external triggers include temperature, magnetic field, ultrasound (US), and light.8,72
pH-Responsive Liposomes
Aerobic glycolysis (the Warburg effect), one of the hallmarks of cancer, states that tumors exhibit increased glucose uptake and lactic acid production, even in the presence of oxygen.73 This increased acid production leads to lower pH levels in cancer cells (pH range of 4.8–6.5).74 Therefore, pH-responsive liposomes are designed to securely store anticancer drugs at physiological pH (∼7.4), but rapidly release the drug below a pH trigger point.72,75
Vila-Caballer et al.76 developed PEGylated pH-responsive liposomes to deliver bovine serum albumin (BSA) to the bladder epithelium. The liposomes were prepared using mPEG5 kDa-DSPE and stearoyl-PEG-poly(methacryloyl sulfadimethoxine) (stearoyl-PEG-polySDM). Confocal microscopy and cytofluorimetry results showed that, at pH 7.4, the internalization of BSA-loaded liposomes by MB49 (mouse bladder carcinoma cells) was remarkably lower than that measured at pH 6.5. Also, control liposomes at pH 7.4 and 6.5 did not deliver BSA to the bladder epithelium in vivo. In contrast, the pH-sensitive liposomes efficiently delivered BSA to MB49 cells at the lower investigated pH. Zhai77 coupled the polypeptide DVar7 with DSPE-PEG2000-MAL to form DSPE-PEG2000-DVar7. DVar7 is a member of the pH-Low Insertion Peptides (pHLIPS) family, which can target the acidic microenvironment of the tumor. The synthesized liposomes were loaded with DOX and then characterized using dynamic light scattering (DLS), ultraviolet (UV) spectrophotometry, and electron microscopy. Following characterization, the acidic-specific uptake of liposomes by tumor cells was investigated using breast cancer (MDA-MB-435S) cells. The prepared pH-sensitive DOX-loaded liposomes had a high encapsulation efficiency (∼98%) and good stability in vitro. In addition, the in vivo studies showed that the pH-responsive liposomes had the best tumor suppression.
Redox-Responsive Liposomes
Another feature of tumors is a reducing microenvironment strictly controlled by the reduction and oxidation states of NADPH/NADP+ and glutathione (GSH, GSH/GSSG).72,78,79 The intracellular concentration of GSH in tumors can reach 10 mM, while the extracellular concentration ranges between 2 and 20 μM.78 Redox sensitivity offers several advantages as a triggering mechanism: first, redox-responsive liposomes are stable in healthy tissues, reducing the toxicity and side effects of both the carrier and payload. Second, they are highly attuned to high GSH concentrations in tumor cells. Finally, the cytoplasm release is theorized to have better therapeutic effects than other locations in the cell.78,80
Wang et al.81 developed redox-responsive liposomes based on a disulfide-derivative paclitaxel-ss-lysophosphatidylcholine prodrug (PTX-ss-PC). The developed liposomes dissociated rapidly in a reduction medium. Additionally, the in vitro cytotoxicity of the liposomes was measured against breast and lung cancer cells. The results showed that the PTX-ss-PC liposomes demonstrated promising GSH-mediated tumor growth inhibition activity. Another study investigating PTX-ss-PC liposomes was conducted by Du et al.82 PTX/SS-LPs were characterized using DLS and TEM. The results of the characterization tests revealed unilamellar vesicles with an average size of 108.6 ± 2.4 nm, which is well within the size range to make use of the EPR effect. The redox-sensitivity of PTX/SS-LPs was confirmed by the changes in the size, morphology, as well as the rapid release of PTX upon the addition of dithiothreitol (DTT). The final release rates indicated that PTX/SS-LPs were responsive to reductive environments. The in vitro studies in MCF-7 and A549 cells showed increased cytotoxicity in the cells treated with PTX/SS-LPs compared to cells treated with control liposomes. In vivo studies were conducted using BALB/c mice; after 3 weeks, the tumor volumes of the groups treated with PTX/SS-LP, PTX/LP were at least 3-fold lower compared to the control group.
Enzyme-Responsive Liposomes
Pathological conditions, such as infection, inflammation, and cancer, lead to an increase in the concentrations of several enzymes at the diseased site. This abnormality can be used to trigger structural changes in enzyme-sensitive liposomes leading to the release of the encapsulated payload.83,84 Shchegravina et al.85 reported phospholipase A2-responsive liposomes incorporating colchicinoid lipid prodrugs in their lipid bilayer. Upon exposure to elevated levels of phospholipase A2, especially sPLA2 analog, the liposomes released colchicinoid-containing fatty acids, which underwent further hydrolysis by nonspecific esterases and released the active species. Ji et al.86 developed β-cyclodextrin (βCD) modified MMP-2 responsive liposomes, integrating antifibrosis PFD and the chemotherapeutic drug GEM for the treatment of pancreatic cancer; the developed system was named LRC-GEM-PFD. The drug release profiles showed that LRC-GEMs released around 75% of the loaded agent after 2 days of the MMP-2 treatment. The tumor penetration of the developed system in vivo was determined by labeling the liposomes with rhodamine (Rhd). Mice xenografted with PSCs/Panc-1 cancer cells were intravenously injected with LRC, free PFD, and LRC-PFD. The average penetration depth of Rhd in each group was 967.8 ± 56.3, 337.8 ± 32.3, and 161.4 ± 16.1 μm for the LRC-PFD, free PFD, and LRC groups, respectively.
Pourhassan et al.87 evaluated the antiproliferative capacity of oxaliplatin (L-OHP) encapsulated in sPLA2 sensitive liposomes in human colon carcinoma (HT-29and Colo205) cell lines. In both tested cell lines, liposomal L-OHP was highly cytotoxic, inhibiting cell growth by 50%. The in vivo studies showed that the sPLA2-sensitive liposomal formulations did not significantly improve the antitumor effect of L-OHP compared to control liposomes. The liposomal formulations demonstrated a minor increase in growth-rate inhibition relative to the free drug; however, all the tested formulations exhibited around 45% treatment-to-control ratios (%T/C) and were therefore statistically insignificant.
Temperature-Responsive Liposomes
Inflammation sites and tumors are characterized by elevated temperatures relative to healthy tissues. Hyperthermia can induce increased tumor tissue permeability, which can lead to enhanced liposome uptake and drug delivery. Release from thermosensitive liposomes can be triggered either through the elevated temperatures which are characteristic of tumors or by externally manipulating the temperature. Thermosensitive liposomes are designed to release their contents at elevated temperatures (around 40–45 °C) through the disruption of the orderly packing of the lipids in the bilayer.
The most commonly used thermosensitive lipid is dipalmitoylphosphatidylcholine (DPPC); an example of a commercially available thermosensitive liposomes (TSLs) includes Thermodox (Celsion, Lawrenceville, NJ, USA).88−90 Several research groups have investigated the use of thermosensitive liposomes in cancer therapy. Motamarry et al.91 used real-time fluorescence imaging to visualize the uptake of thermosensitive liposomal DOX (Thermodox). Nude mice bearing Lewis lung carcinoma cells were injected with Thermodox, and localized hyperthermia was induced by superficially heating the tumors using a probe. In vivo fluorescence imaging was performed before, during, and 5 min following heating. After imaging, the tumors were excised, and the drug uptake was quantified using high-performance liquid chromatography (HPLC). The imaging results showed that the fluorescence of heated tumors increased by 4-fold (after 15 min of heating), 9-fold (after 30 min of heating), and 13-fold (after 60 min of heating) compared to the unheated control tumors. In another study involving Thermodox, Derieppe et al.92 used fibered confocal fluorescence microscopy (FCFM) to monitor the penetration of released-DOX in a subcutaneous rat R1 rhabdomyosarcoma xenograft model. The TSLs were injected intravenously, then the tumor-bearing leg was immersed in a water bath preheated to 43 °C. The real-time FCFM of released-DOX penetration demonstrated an increased fluorescence signal in tumor cell nuclei, indicating an increasing DOX concentration upon cell uptake.
Lyu et al.93 prepared TSLs to deliver an MMP inhibitor, marimastat (MATT), to the tumor microenvironment. The results of in vitro and in vivo studies revealed that TSLs rapidly released their payloads at 42 °C and achieved a 20-fold decrease in tumor growth in mammary carcinoma (4T1) tumor-bearing mice. Furthermore, the developed liposomes reduced MMP-2 and MMP-9 expression in vivo and caused a 7-fold decrease in metastatic lung nodules. Several Thermodox formulations have reached the clinical trial stage; Table 2 presents some clinical trials investigating Thermodox.
Table 2. Summary of Clinical Trials Involving Thermodox (Adapted from Ref (94)).
| title | treatment | cancer | number of participants/estimated enrollment | clinical trial phase | status |
|---|---|---|---|---|---|
| A Phase I/II Study Evaluating the Maximum Tolerated Dose, Bioequivalence/Pharmacokinetics, Safety, and Efficacy of Hyperthermia and ThermoDox (Lyso-Thermosensitive Liposomal Doxorubicin) in Patients With Local-Regional Recurrent Breast Cancer. | Thermodox with microwave hyperthermia (heat) | breast cancer | 17 | I and II | completed |
| Phase II Open-Label Trial of Thermal Ablation and Lyso-Thermosensitive Liposomal Doxorubicin (Thermodox) for Metastatic Colorectal Cancer (mCRC) Liver Lesions | Thermodox | metastatic colorectal cancer (mCRC) | 3 | II | terminated |
| A Phase I Dose Escalation Tolerability Study of ThermoDox (Thermally Sensitive Liposomal Doxorubicin) in Combination With Radiofrequency Ablation (RFA) of Primary and Metastatic Tumors of the Liver | Thermodox | hepatocellular carcinoma | 30 | I | completed |
| PanDox: Feasibility of Enhanced Chemotherapy Delivery to Nonresectable Primary Pancreatic Tumors Using Thermosensitive Liposomal Doxorubicin (ThermoDox) and Focused Ultrasound | Thermodox and FUS | pancreatic ductal adenocarcinoma | 18 | I | not recruiting yet |
| A Pilot Study of Lyso-thermosensitive Liposomal Doxorubicin (LTLD, ThermoDox) and Magnetic Resonance-Guided High Intensity Focused Ultrasound (MR-HIFU) for Treatment of Relapsed or Refractory Solid Tumors | Thermodox and MR-HIFU | solid tumors, soft tissue sarcoma, ewing sarcoma, malignant epithelial neoplasm, rhabdomyosarcoma, Wilms tumor, hepatic tumor, germ cell tumor, bone metastases | 14 | II | not recruiting yet |
| A Phase III, Randomized, Double-Blind, Dummy-Controlled Study of ThermoDox (Lyso-Thermosensitive Liposomal Doxorubicin-LTLD) in Hepatocellular Carcinoma (HCC) Using Standardized Radiofrequency Ablation (RFA) Treatment Time ≥45 minutes for Solitary Lesions ≥3 cm to ≤7 cm | Thermodox | hepatocellular carcinoma | 556 | III | completed |
| A Phase I Study of Lyso-thermosensitive Liposomal Doxorubicin (LTLD, ThermoDox) and Magnetic Resonance-Guided High-Intensity Focused Ultrasound (MR-HIFU) for Relapsed or Refractory Solid Tumors in Children, Adolescents, and Young Adults | Thermodox and MR-HIFU | pediatric cancer, solid tumors, rhabdomyosarcoma, Ewing sarcoma, soft tissue sarcomas, osteosarcoma, neuroblastoma, Wilms tumor, hepatic tumor, germ cell tumors | 34 | I | recruiting |
| Phase II Trial of Phillips MRI-Guided High-Intensity Focused Ultrasound (Sonalleve) and Lyso-thermosensitive Liposomal Doxorubicin (ThermoDox) for Palliation of Painful Bone Metastases | Thermodox and HIFU | painful bone metastases, breast carcinoma, nonsmall cell lung cancer, small cell lung cancer, adenocarcinoma | 0 | II | withdrawn |
| A Proof of Concept Study to Investigate the Feasibility of Targeted Release of Doxorubicin From Lyso-thermosensitive Liposomal (LTSL) Doxorubicin (ThermoDox) Using Focused Ultrasound in Patients With Primary or Secondary Liver Tumors | Thermodox and FUS | liver tumor | 10 | I | completed |
| Heat-Activated Target Therapy (Radiotherapy + Hyperthermia + Lyso-Thermosensitive Liposomal Doxorubicin) of Local-Regional Relapse in Breast Cancer Patients | Thermodox and radiation therapy | breast cancer | 70 | II | suspended |
| A Phase III, Randomized, Double-Blinded, Dummy-Controlled Study of the Efficacy and Safety of ThermoDox (Thermally Sensitive Liposomal Doxorubicin) in Combination With Radiofrequency Ablation (RFA) Compared to RFA-Alone in the Treatment of Non-Resectable Hepatocellular Carcinoma | Thermodox | hepatocellular carcinoma | 701 | III | completed |
| A Phase I, Dose Escalation and Pharmacokinetics Study of Temperature Sensitive Liposome Encapsulated Doxorubicin (ThermoDox) and Hyperthermia in Patients With Local-Regionally Recurrent Breast Cancer | Thermodox | breast cancer | 29 | I | terminated |
Light-Responsive Liposomes
Light-triggered delivery systems are dependent on the penetration depth of the selected light source and the photosensitizing properties of the therapeutic agents.79 Different light wavelengths have been reported as triggers for drug release, including visible, UV, and near-infrared (NIR). The wavelengths preferred in biomedical applications are in the NIR regions (∼700–1100 nm) because at this wavelength the light penetration is more than 1 cm.72
Chen et al.95 designed a NIR responsive bubble-generating thermosensitive liposome (BTSL) system entrapping the reactive carbocyanine dye (Cypate), DOX, and NH4HCO3. Cypate is a NIR fluorescent dye with an absorbance maximum at 778 nm and an emission maximum at 805 nm with a high extinction coefficient of 224,000 (mol/L)−1 cm–1. In vitro release studies showed that the amount of DOX released from BTSL was higher than that of (NH4)2SO4 liposomes at 42 °C. The NIR irradiation caused an increase in temperature, which led to the decomposition of NH4HCO3 and the subsequent generation of many carbon dioxide bubbles; the rise in temperature, in turn, caused the rapid release of drugs from BTSLs.
To address hypoxia-associated photodynamic resistance, an issue commonly encountered in the photodynamic therapy of tumors, Yu et al.96 developed oxygen self-sufficient liposomes containing aza-BODIPY dye (B1), Calcium peroxide (CaO2) NPs in the hydrophobic layer and NH4HCO3 in the hydrophilic cavity (denoted as CaO2/B1/NH4HCO3 lipo). Upon exposure to NIR irradiation, two-photon absorption activated B1 inducing hyperthermia, which further triggered the decomposition of NH4HCO3 into NH3, H2O, and CO2. Subsequently, CO2 reacted with CaO2 to generate oxygen rapidly and self-sufficiently. The developed liposomal system presented a valuable approach to regulating intratumoral hypoxia and overcoming hypoxia-associated photodynamic therapy resistance.
Magnetic-Responsive Liposomes
Magnetic resonance imaging (MRI) is a well-established imaging technique; however, magnetic fields are being used in other biomedical applications, such as controlling drug release from magnetic-field responsive carriers.72 Magnetic nanoparticles (MNPs) are among the promising carriers for magnetic field responsive targeted delivery due to their biocompatibility and unique features.97 Magnetic stimulation can cause release either through localized hyperthermia or through magnetic-field drug targeting.72 Combining MNPs and liposomes was first introduced in 1988 by Marcel De Cuyper and Marcel Joniau.98 Ever since, these “magnetoliposomes” have been used in MRI imaging, targeted drug delivery, and hyperthermia-mediated controlled drug release.79 The most commonly used MNPs in targeted delivery are superparamagnetic iron oxide nanoparticles (SPIONs). Several studies have investigated the use of magnetoliposomes in targeted cancer therapy.
Hardiansyah et al.99 investigated the therapeutic efficacy of DOX-loaded PEGylated magnetic liposomes. The prepared magnetoliposomes exhibited inductive heating from 37 to 56 °C utilizing high-frequency magnetic fields (HFMF). The cytotoxicity studies were conducted using L-929 fibroblasts and HeLa cells. The results of the assay showed that PEGylated magnetic liposomes had no cytotoxicity effects against fibroblast L-929 cells. In contrast, the cytotoxicity of the released DOX to HeLa cells was a function of DOX concentration. Lu et al.100 synthesized TSLs coencapsulating MNPs and Camptosar (CPT-11). This formulation was designed to release its contents upon exposure to a high-frequency alternating magnetic field (AMF). In vitro studies showed that increasing the temperature to 43 °C caused a burst release of CPT-11 from the magnetoliposomes; in addition, the induced magnetic thermal effects lead to a drug release plateau of 97%, in contrast to the 19% release obtained in the absence of AMF.
Ultrasound (US)-Responsive Liposomes
US-mediated drug release from liposomes involves the disruption of the liposomal membrane and occurs in response to either a rise in temperature or the mechanical effects produced by US. With regard to the thermal effects of US, liposomes are stable in the physiological temperature range; however, upon exposure to US, the temperature rises in that area, which disrupts the lipid bilayer, causing the liposomes to release their contents.101,102 Moreover, thermal effects can alter vascular permeability, enhancing the uptake of liposomes. The mechanical effects of US are manifested in the form of acoustic cavitation and sonoporation.
Acoustic cavitation refers to the growth and collapse of microbubbles due to an oscillating pressure field in liquids.103 Sonoporation is the use of sound waves, typically at ultrasonic frequencies, to produce acoustic cavitation to enhance the permeability of the cell plasma membrane.104 Acoustic cavitation is categorized into stable and transient cavitation, both of which are capable of inducing sonoporation. Stable cavitation can create pores by high shear stresses caused by microstreaming around oscillating bubbles, whereas inertial cavitation creates pores by penetration of liquid jets formed by the asymmetric collapse of bubbles near surfaces.105 According to literature, the effect of transient cavitation on drug release is more substantial than stable cavitation because transient cavitation can induce additional mechanical effects such as shockwaves and microjets that complement the effects of sonoporation.101,102,106,107
Xin et al.108 prepared liposomes encapsulating Mitoxantrone (MXT) and PLGA NPs. In their study, the PLGA NPs were used as US-responsive agents instead of conventional microbubbles. The release of MXT-entrapped liposomes was investigated in vitro and in vivo. The cumulative drug release of PLGA NPs encapsulating liposomes was higher than 50% after the application of US, while this value was around 9% without US stimulation. Santos et al.109 developed a system integrating focused US (FUS) with two-photon microscopy (2PM) for the real-time imaging of DOX release from Thermodox during FUS-induced hyperthermia in vivo. The in vivo studies were conducted using a DSWC murine tumor model, and findings indicated that ten 30 s bursts of FUS hyperthermia to 42 °C were able to achieve almost half of the interstitial drug concentration that was observed with a continuous 20 min sonication, which corresponded to an almost 6-fold longer integrated exposure time.
Dual and Multistimuli Responsive Liposomes
A recent advancement in stimuli-responsive drug delivery is the development of dual or multistimuli responsive liposomes. These triggers can be endogenous, exogenous, or a combination of both. Xing et al.110 combined light and temperature triggering to release the contents of their liposomes. The authors synthesized liposomes encapsulating gold nanoparticles (Au NPs) and DOX (Au/DOX-lip). The Au/DOX-liposomes were irradiated with a NIR light, which led to the release of the Au NPs. The Au NPs then penetrated deeper into the tumor tissue; simultaneously, the hyperthermia induced by the irradiation increased the membrane permeability of both the tumor cells and liposomes, facilitating the release and accumulation of DOX in tumor cells. The developed system showed significant antitumor effects, with a tumor growth inhibition rate of around 78%. Zhao et al.111 investigated a pH-temperature dual-sensitive liposome system (CPTLPs) encapsulating the model drug Cytarabine (CYT). In vitro studies showed that CPTLPs had significant pH-temperature sensitivity and prolonged release compared to control liposomes. Moreover, MTT test results showed around 30% higher cell apoptotic effects induced by CPTSLs than the free drug in HepG2 cells. Nezhadali et al.112 developed a pH and temperature-responsive liposomal system coloaded with DOX and mitomycin C (MC). The temperature-sensitive release of the developed system was investigated at different temperatures and pH. At 37 °C and pH 7.4, very low leakage (maximum 15%) was observed, confirming the stability of the prepared liposomes under physiological conditions. At higher temperatures (between 40 and 45 °C), the drug release increased to around 71%. At pH 5.5 and a temperature of 37 °C, drug release was around 45%; however, for higher temperatures (between 40 and 45 °C), the liposomal system achieved its maximum release of 98%. The cytotoxic effect of the DOX/MC co-loaded liposomes was investigated using the MTT assay. The assay was conducted using the NIH3T3 normal fibroblast cell line at pH 7.4 and MCF7 breast cancer cell line at pH 5.5. The MTT results showed that no substantial cytotoxicity was observed for the normal NIH3T3 cell line at concentrations up to 50 μg/mL, indicating that these liposomes were safe for drug delivery usage.
In another study, Chen et al.113 developed pH-sensitive NIR-responsive liposomes coated with pH-sensitive poly(methacryloyl sulfadimethoxine) (PSD) and encapsulating Cypate, DOX, and NH4HCO3 (PSD/DOX/Cypate-BTSL). In a mouse breast (4T1) tumor model, the developed system enhanced cellular uptake and cytotoxicity at a pH of 6.5 when stimulated by NIR irradiation. In vivo results suggested that releasing liposomal contents using NIR can enhance DOX accumulation at the tumor site, antitumor efficacy and reduce the systemic side effects of DOX. Wang et al.114 synthesized gold nanoshell coated chitosan liposomes loaded with Res (GNS-CTS-Res-lips). Res release was triggered using pH and NIR light. First, the pH-mediated release was tested and showed around 57% release of Res at pH 5.0 (compared to a release of 20 percent at pH 7.4). Next, the drug release changes in response to NIR light pulses were investigated; the GNS-CTS-Res-lips were irradiated with NIR at 5 min intervals (at both pH 5.0 and 7.4). Without NIR irradiation, the release was slow and plateaued at about 6% (pH 7.4) and 14% (pH 5.0); however, upon exposure to NIR, the release rate increased to around 40% at pH 7.4 and approximately 80% at pH 5.0.
Shirmardi Shaghasemi et al.115 loaded small unilamellar liposomes with SPIONs and the model drug calcein. The authors hypothesized that the release mechanism involved the local heating of the embedded SPION through Néel relaxation in an AMF. The release results showed that the concentration of SPIONs in the membrane is a determining factor for calcein release from liposomes when exposed to an AMF. At a 2 wt % SPION concentration, only 28% of calcein was released after the first pulse (duration of 2 min), and 40% after 5 pulses. When the concentration was increased to 4 wt % SPION, the first 2 min pulses released around 48% of the payload. Moreover, only three pulses were required to reach maximum release of calcein, which was approximately 90%. Table 3 presents a summary of some other relevant studies.
Table 3. Summary of Recent Studies Focusing on Dual/Multi-Stimuli Responsive Liposomesa.
| stimuli | payload | cancer cell line | animal model | main findings | ref |
|---|---|---|---|---|---|
| pH and temperature | Cytarabine | human hepatoma (HepG2) cells | n/a | (1) CPTLPs had significant pH-temperature sensitivity and prolonged release compared to control groups | (111) |
| (2) MTT tests results showed 30% higher cell apoptotic effects induced by CPTSLs than free drug in HepG2 cells | |||||
| pH and temperature | DOX and mitomycin C (MC). | normal fibroblast (NIH3T3) cell line and breast cancer (MCF7) cell line | n/a | (1) at 37 °C and pH of 7.4, lowest release (maximum 15%) was observed. While highest release of 98% was achieved at pH 5.5 and temperatures (between 40 and 45 °C) | (112) |
| (2) MTT results showed no substantial cytotoxicity for the normal NIH3T3 cell line indicating that these liposomes were safe for drug delivery usage | |||||
| temperature and magnetic | Fe3O4 MNPs and DOX | cervical carcinoma (HeLa) cells | n/a | (1) DOX released from the MagABC liposomes at 37 °C was about 20%; however, at 42 °C, it increased to approximately 45% | (143) |
| (2) relative fluorescence intensity of HeLa cells was 7.5% and 64.2% after incubation with the MagABC liposomes at 37 and 42 °C, respectively, compared to 11.1% and 19.9% for ABC liposomes alone | |||||
| NIR light and temperature | DOX and Au NPs | cervical carcinoma (HeLa) cells | female Kunming mice | (1) tumor inhibition rate of Au/DOX-Lips NIR reached 85.81%, which was higher than that of Au/DOX-Lips (56.85%) and free DOX (35.37%) | (110) |
| pH and NIR light | Cypate, DOX, and NH4HCO3 | mammary carcinoma (4T1) cells | female BALA/c nude mice | (1) at pH 5.0, the DOX release (after NIR exposure) from PSD/DOX/Cypate-BTSL and PSD/DOX/Cypate-L were 87.8% and 52.7% respectively | (113) |
| NIR light, temperature, and pH | Res | cervical carcinoma (HeLa) cells | n/a | (1) about 57.6% of Res was released at a pH of 5.0 compared with only 20.5% at pH 7.4 | (114) |
| (2) without NIR, the release from GNS-CTS-Res-lips was only 5.7% (pH 7.4) and 13.7% (pH 5.0) | |||||
| temperature and magnetic | SPION and calcein | n/a | n/a | (1) therapeutic value of Res and NIR was 57.3%, which is higher than that of Res alone (29.6%) or sole photothermal therapy (42.6%), but lower than the measured therapeutic efficacy of the Res-NIR-Temp-pH treatment group (81.1%), proving the distinct, synergistic effect of chemophotothermal therapy in vitro | |
| (2) For 4 wt % SPIONs, ∼ 90% of calcein was released while when 2 wt % SPION were incorporated, only 28% was released | (115) | ||||
| NIR light and temperature | Cisplatin and ICG | breast cancer (MDA-MB-231) cells | n/a | (1) liposomes showed improved inhibitory effect (3.05% cell viability) with added NIR, compared to free cisplatin (28.41%) or treatment without NIR (11.24%) | (144) |
| magnetic and enzyme | ICG | oral squamous cell carcinoma (SCC9) cells and hypopharyngeal squamous cell carcinoma (UDSCC2) cells | NMRI-Foxn1nu/foxn1nu female Mice | (1) AMF with SMase increased the FMT fluorescence compared with only SMase | (145) |
| (2) UDSCC2 cells are significantly more sensitive than SCC9 in trigging ASMase activity under high doses of irradiation | |||||
| (3) significant increases of SMase activity and decrease of cell viability were observed with treatment time at higher dose cisplatin | |||||
| NIR light, pH, and temperature | OA | human osteosarcoma (143B) cells | (1) at pH 7.4, the release rates of GNOLs reached 42 ± 1%, but at pH 5.5 they release 53 ± 1% | (146) | |
| (2) drug release rate of the NIR group reached 92 ± 1%, while the non-NIR group was only 69 ± 1% | |||||
| (3) 143B cells treated with GNOLs exhibited tumor inhibition rates of 73.74 ± 1.32%. | |||||
| (4) inhibition rates of GNOLs were 73.74 ± 1.32% without NIR and 86.91 ± 2.53% with NIR | |||||
| (5) In in vivo experiments with GNOLs and NIR showed the highest antitumor effect with an inhibition rate of 79.65% | |||||
| NIR light and temperature | Sunitinib and IR780 dye | mammary carcinoma (4T1) cells and human umbilical vein endothelial (HUVEC) Cells | syngeneic female BALB/c | (1) less than 30% was released from Lip-IR780-Sunitinib in medium with a pH of 5.0, 6.8, or 7.4 indicating the stability of liposomes under different pH conditions | (147) |
| (2) release with NIR was about 3-fold higher than that without laser (from 11.6% to 33.6%) | |||||
| (3) cell viability of Lip-IR780 NIR and Lip-IR780-Sunitinib with NIR dropped to about 50% | |||||
| (4) Sunitinib/laser was the most effective at suppressing tumor angiogenesis among all the treatment groups (MVD of 80.7%) | |||||
| pH and temperature | DiIC18(5) and Calcein | human hepatoma (HepG2) cells | n/a | (1) release of liposomes from the hydrogel was temperature and enzymatic responsive | (148) |
| pH and temperature | DOX | human aortic adventitial fibroblasts (AoAF) and murine NIH3T3 cells | n/a | (1) enzymatic degradation began several hrs after exposure to MMP-1, while DOX release occurred almost immediately following hyperthermic stimulus, with complete release after 48 h | (149) |
Abbreviations: Au NPs, gold nanoparticles; NIR, near-infrared; Res, resveratrol; n/a; not applicable; SPION, superparamagnetic iron oxide nanoparticles; ICG, indocyanine green; AMF, alternating magnetic field; MNP, magnetic nanoparticle; MagABC, magnetic ammonium bicarbonate; CPT-11, camptosar; TML, thermosensitive magnetic liposome; OA, oleanolic acid; GNOL, gold nanoshells coated oleanolic acid loaded liposome; MVD, microvessel density; DiIC18(5), 1,1-dioctadecyl-3,3,3,3-tetramethylindodicarbocyanine perchlorate.
Combining Surface Functionalization and Stimuli-Mediated Release from Liposomes
The development of stimuli-responsive liposomes modified with different moieties to target receptors overexpressed on cancer cells or in the tumor microenvironment is a recent and promising approach to maximize the benefits of targeted cancer therapy. Lee et al.116 synthesized HA grafted DTX loaded pH-responsive liposomes. Functional 3-diethylaminopropyl (DEAP) groups were used to make a pH-responsive polymer; three liposomal formulations with three different molar ratios of DEAP to HA were prepared, namely, HA-g-DEAP0.15, HA-g-DEAP0.25, and HA-g-DEAP0.40. Out of the three formulations, HA-g-DEAP0.40 gave the best results in terms of release of the encapsulated DTX in response to pH reduction to endosomal pH (i.e., 6.5). Moreover, HA liposomes were effective at entering the human colon carcinoma (HCT-116) cells with a CD44 receptor overexpression causing a significant increase in HCT-116 tumor cell death.
Yang et al.117 developed asparagine-glycine-arginine (NGR) peptide modified thermosensitive liposomes containing a reducible siRNA-CPPs for tumor-specific siRNA transfection (siRNA-CPPs/NGR-TSL). The developed liposomal system had a particle size of about 90 nm, and a %EE of approximately 86%. In the in vitro studies, both the preheated free siRNA-CPPs and siRNA-CPPs/NGR-TSL silenced the c-myc regulator gene in human fibrosarcoma (HT-1080) cells; however, when tested in vivo, siRNA-CPPs/NGR-TSL displayed about 3-fold better antitumor efficacy and around 2-fold superior gene silencing efficiency compared with free siRNA-CPPs under hyperthermia. Table 4 presents a summary of some recently published studies focused on the use of surface functionalization and stimuli responsiveness in a single liposomal formulation for the efficient delivery of anticancer therapeutics.
Table 4. Summary of Recent Studies Focusing on Stimuli-Triggered Targeted Liposomesa.
| stimuli | moiety | payload | cancer cell line | animal model | main findings | ref |
|---|---|---|---|---|---|---|
| magnetic and temperature | CET | CPT-11 and citric acid-coated Fe3O4 MNPs | human primary glioblastoma (U87) cells | Balb/c nude mice | (1) around 19% CPT-11 was released in vitro without AMF, contrastingly around 97% drug released with AMF (at 43 °C) | (100) |
| (2) cell viability of the TML-CPT-11 group was reduced from ∼80% (37 °C) to ∼40% (43 °C) | ||||||
| (3) median survival time of control and TMLCET was 20 and 21 days, respectively; for CPT-11 loaded liposomes, TML-CPT-11 and TML-CPT-11- CET groups showed median survival times of 27 and 28 days, respectively; the median survival increased to 30 days with magnetic guidance, which further increased to 33.5 days when augmented with AMF treatment | ||||||
| pH | HA-g-DEAP | DTX | human colon carcinoma (HCT-116) cells | n/a | (1) compared to HA-g-DEAP0.15 and HA-g-DEAP0.25, HA-g-DEAP0.40 was the best pH responsive formulation | (116) |
| (2) HA-g-DEAP0.40-lip displayed a higher cumulative DTX release at pH 6.5 than that at pH 7.4 | ||||||
| (3) TX-loaded HA-g-DEAP0.40-lip significantly reduced cell viability in HCT-116 cells | ||||||
| (4) HA-g-DEAP0.40-lip showed the highest hemolysis effect at pH 6.5 | ||||||
| pH | ErbB2 antibody Fab | DOX | breast cancer (HCC1954) and (MDA-MB-468) cells | female BALB/c nu/nu mice | (1) cell association of Fab′-GGLG liposomes increased 10-fold in comparison to GGLG liposomes | (150) |
| (2) significantly enhanced tumor growth inhibition was obtained in an ErbB2-overexpressing breast cancer-bearing mouse model | ||||||
| US | iRGD | DOX | mammary carcinoma cells (4T1), human breast adenocarcinoma (MCF-7) cell and human umbilical vein endothelial (HUVEC) Cells | n/a | (1) DOX from iRGD-LTSL-DOX rapidly penetrated tumor interstitial space after HIFU-triggered heat treatment | (151) |
| US | 111In-EGF | DOX | human breast cancer (MDA-MB-468 and MCF7) cells | female athymic nude mice | (1) cell killing was higher in MDA-MB-468 than in MCF7 cells | (152) |
| (2) increased tumor uptake by 66% in the MDA-MB-468 cell line | ||||||
| US | HSA | calcein | breast cancer cell lines (MDA-MB-231 and MCF-7) | n/a | (1) calcein uptake by the cancer cells was enhanced following sonication | (153) |
| US | ES | calcein | breast cancer (MDA-MB-231 and MCF-7) cells | n/a | (1) exposure to LFUS revealed an enhanced calcein uptake by the cells | (154) |
| pH | H7K (R2)2 peptide | DOX | rat glioma (C6) cells and human glioblastoma (U87-MG) cells | orthotopic tumor-bearing nude mice | (1) for DOX-PSL-H7K(R2)2 and DOX-PSL groups, the release of DOX in pH 5.5, 6.0, and 6.5 buffer solutions were faster than that in pH 7.4 | (155) |
| (2) cellular level for coumarin-6-PSL-H7K(R2)2 and coumarin-6-PSL was about 1.7- and 1.2-fold higher than that for coumarin-6-SSL at pH 6.8; however, at pH 7.4, the fluorescence of coumarin-6-PSL-H7K(R2)2, coumarin-6-PSL and coumarin-6-SSL was almost identical | ||||||
| (3) median survival time of mice treated with DOX-PSL-H7K(R2)2 (39 days) was longer than that of mice treated with DOX-SSL (31 days) and DOX-PSL (35 days) | ||||||
| redox | HA | DOX | osteosarcoma (MG63) and liver (LO2) cells | BALB/c nude | (1) in the medium without GSH, only 30% was released from the HA-lip, adding 20 μM GHS increased the release to 32.8%; however, adding 10 mM GHS triggered a burst release of DOX with >60% | (156) |
| (2) liposomes had more pronounced cytotoxicity to MG63 cells than to normal liver cells | ||||||
| (3) Chol-SS-mPEG/HA-L resulted in most significant inhibition of tumor growth compared with all other liposomes or free DOX | ||||||
| pH | polyarginine | siRNA | breast cancer (MCF-7) and human lung carcinoma (A549) cells | n/a | (1) when pretreated under acidic conditions (pH 6.2), siRNA-loaded liposomes showed elevated level of cellular uptake and apoptosis compared to those incubated at pH 7.4 | (157) |
| (2) results of cell uptake, apoptosis, and gene expression analyses under acidic conditions for the ACPP-L group were not comparable to those of the CPP-L group | ||||||
| pH and magnetic | H7K(R2)2 | PTX | human breast carcinoma (MDA-MB-231) cells | female BALB/c nude mice | (1) released PTX from PTX/SPIO-SSL-H7K(R2)2 in both buffer solutions of pH 6.8 and 7.4 was almost identical | (158) |
| (2) IC50 value of the PTXSSL-H7K(R2)2 group at pH 6.8 (7.24 ± 0.57 μM), was significantly reduced, compared with that at pH 7.4 (31.97 ± 4.94 μM) | ||||||
| (3) tumor growth inhibition in the PTX-SSL-, PTX/SPIO-SSL-, and PTX/SPIO-SSL-H7K(R2)2 groups was about 70%, 70%, and 90%, respectively | ||||||
| pH | RGD and [D]-H6L9 | PTX | colon carcinoma (C26) and breast cancer (MCF-7) cells | Balb/C mice | (1) under pH 6.3, (R+D)-Lip could be taken up by C26 cells with improved efficiency | (159) |
| (2) (R+ D)-Lip resulted in significant tumor growth suppression | ||||||
| (3) body weights of all groups hardly dropped during the treatment, implying that all the PTX-loaded liposomes showed little in vivo toxicity | ||||||
| pH and enzyme | anti-PD-L1 peptide and MMPs responsive moiety | DOX | mouse melanoma model (B16F10) cells | female C57BL/6 mice | (1) LPDp achieved the optimal tumor suppression efficiency (∼78.7%), which demonstrated the significantly enhanced antitumor effect than that of LPp (∼57.5%) as well as that of LD (<40%) | (160) |
| pH | CD25 antibody | IL-2, PD-L1, and IQ | lung metastasis tumor (B16BL/6) model cells | C57BL6 mice | (1) CD25-Lipo (IL/PL/IQ)+Treg cells suppressive effect on effector CD4+ T cell proliferation was 77.0% which was similar to the control group (79.4%) without Treg cells; however, iso-Lipo (IL/PL/IQ) + Treg cells and Treg cells alone, reduced the percentage of proliferation to 47.5 and 49.4%, respectively | (161) |
| (2) lower tumor weight was identified in mice treated with CD25- Lipo (IL/PL/IQ) Treg compared to those treated with isoLipo (IL/PL/IQ) plus Treg | ||||||
| redox and pH | CS and HA | IAP inhibitor survivin-shRNA gene and HAase | human breast cancer (MDA-MB-231 and MCF-7) cells and mouse embryonic fibroblast (NIH/3T3) cells | BALB/c nude mice | (1) uptake of HCLR incubated in pH 6.5 was ∼85%, which was greater than that in pH 7.4 | (162) |
| (2) viability of cells treated with HCLR decreased to 63%, lower than that of HLR (81%) and LR (66.3%); negative control groups of HCLR and HLR both exhibited cell viability ∼95% | ||||||
| (3) Tumor size in the HLR group was nearly 2 times larger than that of the HCLR group, while tumor size in LR and saline groups were nearly 4 times larger | ||||||
| magnetic | Oct and Fe3O4 MNPs | OA | human lung carcinoma (A549) cells and cervical carcinoma (HeLa) cells | Female Kunming mice | (1) mean inhibition rates of OA-lips, OA-Olips, and OA-OMlips in A549 cells were 82.51, 90.06 and 89.76%, respectively; there was no significant difference for HeLa cells under the same conditions, and their mean inhibition rates were 83.82, 85.18 and 84.68%, respectively | (163) |
| (2) growth of the tumors was significantly inhibited in the OA-OMlips (with magnet) group compared with the groups treated with other formulations | ||||||
| redox | ES and COS | DOX | osteosarcoma (MG63) cells and liver (LO2) cells | male BALB/c nude mice | (1) cellular uptake rates were ranked in order: free DOX > Chol-SS-COS/ES-Lp > Chol-SS-COS-Lp > Chol-COS-Lp for both cells | (164) |
| (2) tumor weights (g) were measured as 2.84 ± 0.23, 1.90 ± 0.16, 1.38 ± 0.13, 1.12 ± 0.02 and 0.70 ± 0.12 for the groups treated with normal saline, free DOX, Chol-COS-Lp, Chol-SS-COS-Lp and Chol-SS-COS/ES-Lp, respectively | ||||||
| NIR light and temperature | FA | Au NRs and DOX | mouse breast cancer (4T1) cells and mouse origin fibroblast (NIH3T3) cells | Balb/c mice | (1) 5 min NIR pulses triggered DOX release, reaching 46.38% in 60 min at pH 5.5 | (165) |
| NIR light and magnetic | HA | DTX and citric acid coated MNPs | breast cancer (MCF-7) cells and mouse origin fibroblast (NIH3T3) cells | n/a | (1) under NIR irradiation the HA-MNP-LPs released over 20% more drug than the nonirradiated liposomes | (166) |
| (2) IC50 values of free DTX, DTX/MNP-LPs, DTX/HA-MNP-LPs and the irradiated group were 8.93 ± 2.64, 2.37 ± 0.18, 414 1.35 ± 0.34, and 0.69 ± 0.10 μg/mL respectively | ||||||
| US | RGD, HSA and ES | calcein | n/a | n/a | (1) results suggest that the AKF is adept at handling drug release estimation problems with a priori unknown or with changing noise covariances | (167) |
| (2) AKF approach exhibited a 69% reduction in the level of error in estimating the drug release state | ||||||
| US | Tf, RGD, and HSA | calcein | n/a | n/a | (1) Pegylated liposomes were more sonosensitive compared to nonpegylated liposomes when exposed to LFUS | (168) |
| (2) HSA-PEG and Tf-PEG liposomes were more sonosensitive compared to the control pegylated liposomes upon exposure to LFUS | ||||||
| US | folate | PFC5 emulsions, calcein, and model GFP plasmid | cervical carcinoma (HeLa) cells | n/a | (1) application of LFUS enhanced the drug delivery and plasmid transfection | (139) |
| (2) delivery of therapeutics appears was to the cytosol, indicating that the expansion of the emulsion droplets disrupted both the eLiposomes and the endosomes | ||||||
| US | HA | calcein | breast cancer cell line (MDA-MB-231) and NIH-3T3, an embryonic mouse fibroblast | n/a | (1) LFUS triggered HA liposomes showed a significant enhancement of calcein uptake by MDA-MB-231 cells compared to calcein uptake without US | (169) |
| temperature and magnetic | MAB1031 antibody | DOX and gadolinium-chelate | breast cancer (MDA-MB-231) cells | n/a | (1) DOX release from LipTS–GD–MAB at 37 °C, was about 21.7 ± 3% after 24 h | (170) |
| (2) DOX release at (39–40 °C) was rapid reaching about 78% and 88% after 1 h, respectively | ||||||
| (3) increase in fluorescence after treatment with LipTS–GD–MAB was observed, indicating effective cellular binding | ||||||
| pH | FRβ | doxycycline (anti-CAPN2) and DTX | lung adenocarcinoma (PC-9, NCI-H1650 and A549-Luc) cells | male Balb/c nude mice | (1) after treatment with A549-Luc cells, the FRβ-pH lipo-Cy5.5 showed 7.23- and 10.93-fold stronger fluorescence signals compared to NH2-pH lipo-Cy5.5 and control, respectively | (171) |
| (2) in vivo, the DTXL/DOXY lipo-treated group showed a significant tumor growth inhibitory effect compared to the other treatment groups | ||||||
| US | FA | MnP | mouse breast cancer (4T1) cells | female Balb/c mice | (1) FA-MnPs showed higher cellular uptake than MnPs | (172) |
| (2) 85% of 4T1 cells in the FA-MnPs + US group were killed, suggesting excellent SDT effect | ||||||
| (3) strong 1O2 signal occurred in the right tumor in FA-MnPs + US(s) group, suggesting good SDT efficiency of FA-MnPs, while no obvious 1O2 signal was observed in the left tumor (no US treatment) | ||||||
| (4) tumors in FA-MnPs + US groups were effectively suppressed due to efficient SDT |
Abbreviations: CET, cetuximab; HA-g-DEAP, hyaluronic acid grafted with functional 3-diethylaminopropyl; DTX, docetaxel; GGLG, 1,5-dihexadecyl N,N-diglutamyl-lysyl-l-glutamate ; 111In-EGF, indium-111 tagged epidermal growth factor; HSA, human serum albumin; ES, estrone; HA, hyaluronic acid; ACPP, activatable cell penetrating peptide; PTX, paclitaxel; MMP, matrix metalloproteinase; LPDp, polymer-liposomes grafted with anti-PD-L1 peptide and loaded with DOX; LPp, polymer liposomes grafted with peptide; IL-2, interleukin-2; PD-L1, programmed cell death ligand 1 antibody; IQ, imiquimod; CS, chitosan; HAase, permeation promoter hyaluronidase; LR, DOTAP/survivin-shRNA; LPR, CS/DOTAP/survivin-shRNA lipopolyplex; CLR, HAase/CS/DOTAP/survivin-shRNA; HCLR, HA/HAase/CS/liposome/survivin-shRNA; OMlips, octreotide-modified magnetic liposomes; Oct, octreotide; ES, estrogen; COS, chotooligosaccharides; ICG, indocyanine green; poly I:C, polyinosinic:polycytidylic acid; FA, folic acid, Au NRs, gold nanorods; CPT-11, Camptosar; AKF, adaptive Kalman filter; LFUS, low-frequency ultrasound; MnP, manganese-protoporphyrin.
Future Prospects
Despite the reported preclinical successes of liposomal drug delivery systems, their real impact in cancer therapy currently remains limited. This is often attributed to the fact that the field is a relatively new area of science.118 Some studies have suggested that this limited therapeutic efficacy is mainly due to formulation design and tumor pathophysiology, which may be sufficiently different in humans than in the animal models employed in research.119,120
As mentioned earlier, the initial enthusiasm that promoted the development and success of nanomedicine can be ascribed to the discovery of the EPR effect. However, inter- and intratumoral variability as well as tumor variability as a function of cancer type and among patients has been shown to limit the efficacy of the EPR effect, foster drug resistance, and complicate the selection of globally effective therapeutic agents.121,122 Some of the methods proposed to address tumor heterogeneity and its implications on liposomal anticancer drug delivery include the modulation of tumor vasculature by increasing the blood pressure of a patient.119,123 For example, hypertension caused by the systemic administration of angiotensin-II (AT-II) leads to the passive opening of pores in the tumor endothelium, which may improve the delivery of liposomes to tumor sites.124 Increasing vascular permeability using nitric oxide (NO)-releasing/inducing agents (e.g., nitroglycerin) can also contribute to augmenting the EPR effect. These agents liberate nitrite, which is converted to NO under the hypoxic conditions of tumor tissues. Administration of NO-releasing agents should thus release NO and enhance the EPR effect by inducing vasodilation.119,124
Moreover, simultaneously targeting at the vascular, tissue, and cellular levels has been suggested as a viable approach to enhance the EPR effect and overcome cancer MDR. Multitier targeting can be achieved using more than one antineoplastic agent, and liposomes have shown effective coloading and a sustained release of several anticancer agents.119,123 However, a commonly encountered issue with the coloading of liposomes is the low water-solubility of one or both anticancer medications, which can lead to reduced liposomal loading capacity and poor stability. In such cases, coadministration should be explored for effective multiagent delivery. Although the active drug loading method effectively uses the electrostatic gradient across the lipid bilayer as a driving force to load drugs into liposomes, this method is more applicable to amphiphilic soluble drugs. Solvent-assisted active loading technology (SALT) is an advancement of the active loading method to improve encapsulation efficiency and formulation stability.125,126
In addition to targeting resistance pathways and metabolic modifications commonly implicated in MDR, the characteristics of the tumor could be used to design personalized treatment options. Biomarkers such as tumor-specific protein overexpression and mutations in driver genes are currently used to predict tumor response to selective targeted therapies, with additional biomarkers rapidly emerging. Therefore, biomarker-specific treatment plans can be tailored to each patient according to their tumor molecular profile.127,128 For example, the I-PREDICT study involved customized therapies based on molecular profiling of cancer patients.129 The underlying hypothesis is that solely targeting one molecular alteration of a tumor is often insufficient to yield improved responses. Moreover, precision medicine oncology trials have been focused so far on molecular matching with predetermined monotherapies. However, several trials exhibited low matching rates, often in the range of 5–10%.127,128 A recent study took into account several actionable molecular alterations and proposed customized multidrug regimens to achieve durable antitumor activity.129
Liposomes can be an ideal candidate for rapid preparation of a therapeutic regimen for personalized medicine, using “plug-and-play” liposomes. Such liposomes would come preloaded with therapeutics and have surface chemistries to which selective target-seeking ligands can be attached by simple mixing in the clinic, followed by spin-column separation and immediate use. There are many surface chemistries that can be explored, such as liposomes decorated with sulfhydryl-terminated PEG chains. Sulfhydryls react easily with maleimides, haloacetyls, disulfides, and more, which can already be attached to targeting groups.
Another promising aspect of precision medicine is personalized dosing regimens tailored to a patient’s tumor profile, including liposome penetration in tumor tissue.130,131 Before treatment, noninvasive imaging techniques using liposomes loaded with model dyes or radiolabeled markers can be used to assess the heterogeneity of the tumor and detect the penetration of the liposome at the tumor site. Moreover, liposome accessibility of the tumor microenvironment (e.g., vascular and lymphatic architecture) may provide information useful in drug selection and predicting drug behavior.130 Such “scouting” liposomes, which might even be loaded with X-ray or MRI contrast agents, can be combined with CT or MR imaging to predict and calculate liposomal penetration and therapeutic delivery a priori as part of personalized medicine. Several other conventional imaging modalities (e.g., PET or SPECT) might be applied, and even novel imaging techniques (e.g., dual-energy CT, diffusion-weighted MRI, and bioluminescence imaging) could be investigated for liposomal applications.132,133 During treatment, plasma pharmacokinetic (PK) sampling can be performed to validate bioavailability in the blood and support models of liposomal delivery to tumor tissues.134 All this information can then be integrated with preclinical and prior knowledge using mathematical models and computer simulations to determine the dosing regimen and further adapt the treatment plan.130
Other strategies to overcome MDR and enhance the liposomal delivery of chemotherapeutics to cancer cells include the use of external stimuli. As mentioned previously, US is of special interest because it is noninvasive, can be controlled both spatially and temporally, and can penetrate deep into the body. Given the promise of US as a triggering mechanism for liposomal release, a great deal of focus has been placed on the optimization of US exposure parameters (i.e., frequency, intensity, negative pressure, duration, and duty cycle).
Another object of intense research is liposomal gene delivery for cancer therapy. Different approaches have been investigated for cancer gene therapy; these include the induction of apoptosis, immune modulation, correction of gene defects, inhibition of tumor invasion, and gene therapy to improve chemo- and radiotherapy.135 DNA and RNA can be carried on the surface of, or within, a liposome. For example, complexation of DNA to the bilayer of cationic liposomes has been shown to deliver DNA to cells.136 More recently, plasmids dissolved in the liposome interior have been delivered,137 and sometimes actively released by ultrasound,138,139 and even actively targeted with transferrin.140 Another exciting aspect of gene therapy is immunotherapy. Liposomes have been used to deliver RNA to activate an immunotherapeutic response141 or to deliver agents that upregulate the immune system. The possibilities seem endless.142
Conclusion
Encapsulating anticancer therapeutics in nanocarriers has proven to be a promising alternative to the conventional cancer treatment methods, as it improves both the safety and efficacy of anticancer therapeutics. Several liposome formulations are commercially available in the market, e.g., Doxil, DaunoXome, and Depocyt. Surface functionalization and various stimuli have been introduced to overcome the limitations of conventional liposomes and further enhance their therapeutic efficacy. This review highlighted some of the recent advances in surface functionalization and optimization of liposomes to allow the delivery of chemotherapeutics locally upon internal and/or external stimulation. In addition, we presented an overview of relevant in vitro and in vivo studies pertaining to ligand-targeted and stimuli-responsive liposomes.
Acknowledgments
The authors would like to acknowledge the financial support of the American University of Sharjah Faculty Research Grants (FRGs and eFRGs), the Al-Jalila Foundation (AJF 2015555), the Al Qasimi Foundation, the Patient’s Friends Committee-Sharjah, the Biosciences and Bioengineering Research Institute (BBRI18-CEN-11), the Technology Innovation Pioneer Healthcare Awards, Takamul, Sheikh Hamdan Bin Rashid Al Maktoum Award for Medical Sciences (MG-57-2020), and the Dana Gas Endowed Chair for Chemical Engineering.
Author Contributions
The manuscript was written through the contributions of all authors. All authors have given approval to the final version of the manuscript.
The authors declare no competing financial interest.
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