Platinum-based combination nanomedicines for cancer therapy

Abstract

The relatively low success rate of cancer nanomedicines has raised debate on the roles of the enhanced permeability and retention (EPR) effect in enhancing drug delivery to tumors and improving therapeutic efficacy. In this review, we highlight new strategies beyond the EPR effect for enhancing nanoparticle delivery to tumors. We discuss the roles of transcellular extravasation, receptor-mediated pathways, and protein corona interactions on nanoparticle deposition in tumors. We summarize recent progress in platinum-based combination nanomedicines containing multiple chemotherapeutics with synergistic anticancer mechanisms and multiple anticancer therapies with novel mechanisms to enhance drug delivery and antitumor activities. We also highlight future opportunities in platinum-based combination nanomedicines and key hurdles for the translation of these combination nanomedicines into the clinic.

1. Introduction

As one of the biggest threats to public health, cancer causes approximately 10 million annual deaths worldwide[1]. Despite the development of novel cancer therapies with distinct anticancer mechanisms[2], chemotherapy remains an important treatment modality for many cancer patients. Most chemotherapy regimens contain multiple drugs to synergistically kill cancer cells and overcome resistance[3,4]. However, combination therapy also exacerbates the side effects of each drug to cause debilitating adverse events. Many approaches have been developed to reduce toxicity, increase tolerance, and/or enhance the efficacy of chemotherapeutics, including the development of prodrugs that can be preferentially activated in tumors[5], structural modification of parent drugs to increase potency[6], conversion of insoluble hydrophobic drugs to hydrophilic prodrugs[7], and the formulation of chemotherapeutics into nanoparticles[8].

Liposomal nanoparticles have been widely used to deliver chemotherapeutics[9]. The postulation of the enhanced permeability and retention (EPR) effect of nanoparticles by Matsumura and Maeda has spurred the development of numerous nanoparticle chemotherapeutics to improve pharmacokinetic (PK) properties and tumor deposition of drug payloads.[10–14] Despite extensive efforts, only a small number of chemotherapeutic nanomedicines, including Doxil, DaunoXome, Depocyt, Abraxane, Onivyde[15], and Vyxeos, have been approved by the Food and Drug Administration for cancer treatment[16–18], which has led some researchers to question the prevalence of the EPR effects in human tumors[19]. Other researchers observed that the existing nanomedicines reduced general toxicity but did not provide survival benefits to human patients[17,20]. However, Vyxeos showed a 3-month survival benefit over the traditional daunorubicin and cytarabine combination in patients with secondary acute myeloid leukemia[21].

The significant survival benefits of Vyxeos suggest new opportunities for the development of combination nanomedicines. As the most clinically used chemotherapy, platinum-based drugs, including cisplatin, carboplatin, and oxaliplatin, have been formulated into many nanoparticles. Several of them have undergone clinical evaluations[22], but none have been approved for clinical use. As platinum drugs are almost always used in combination with other drugs, there has been significant interest in developing platinum-based combination nanomedicines to improve efficacy and reduce systemic toxicity.

In this review, we discuss the strategies for enhancing nanoparticle delivery to tumors, with discussions on the EPR effect, transcellular extravasation, receptor-mediated pathways, and protein corona interactions. We summarize the development of platinum-based drugs and nanotherapeutics, with particular emphasis on platinum-based combination nanomedicines containing multiple chemotherapeutics for improved antitumor efficacy. We also highlight future opportunities in and key hurdles for the translation of combination nanomedicines into the clinic.

2. Enhancing drug delivery to tumors

Nanomedicines can increase drug accumulation in tumors for better efficacy and decrease drugs in healthy tissues to reduce side effects[17]. While the EPR effect has been invoked for the improved performances of nanomedicines over their parent drugs, recent experimental evidence has sparked debate on the significance of the EPR effect on enhanced drug delivery to tumors. In this section, we will discuss the roles of the EPR effect, transcellular extravasation, receptor-mediated pathways, and protein coronas on nanoparticle depositions in tumors. We will also discuss the opportunities to leverage these effects for clinical translations of nanomedicines.

2.1. The EPR effect

With the assumption that nanoparticles can cross abnormal and leaky tumor blood vessels and retain in the tumors due to the ineffective lymphatic drainage of tumor tissues, the EPR effect has provided the impetus for developing passive tumor-targeted nanoparticles [23]. To maximize the EPR effect, nanoparticles of 10–200 nm in dimensions are designed to avoid renal clearance of ultrasmall nanoparticles (<10 nm) as well as the entrapment of large particles (> 200 nm) in livers and spleens. The surfaces of these nanoparticles are coated with anti-fouling agents to reduce plasma protein binding, thus minimizing mononuclear phagocytic system (MPS) uptake. Long-circulating nanoparticles can exploit the EPR effect to increase tumor accumulation. By analyzing the delivery efficiency of nanoparticles in 232 data sets, Wilhelm et al. found a median of 0.7% injected doses accumulated in the tumors.[24] Based on this analysis, the authors conjectured the insignificant roles of the EPR effect in tumors[25]. However, many factors are convoluted in these datasets. Many of these nanoparticles did not have the long-circulating property to exploit the EPR effect. Material compositions, particle morphologies, and other factors could also have adversely impacted the tumor delivery efficiency of these nanoparticles.

2.2. Transcellular extravasation

While the EPR effect uses intercellular extravasation through the gaps between adjacent endothelial cells, nanoparticles can extravasate into tumors via an active transendothelial pathway. In endothelial cells, vacuolar organelles are interconnected and span from the lumen to the albumen for active transportation. In abnormal tumor blood vessels, the number of vesicles available for transendothelial transport is reduced, but the distance they need to travel across is also reduced due to the thinned endothelium[24]. Sindhwani et al.[26] showed that tumor vessels have a lower frequency of intracellular gaps compared to intercellular gaps and transcellular channels (Figure 1a). Nanoparticles can extravasate via active transendothelial pathways, such as through fenestrae and vacuoles (Figure 1b). By using Zombie animal models, they found up to 97% of nanoparticles entered tumors via the active trans-endothelial pathway (Figure 1c). They also found that the gaps are also rare in tumor vessels from cancer patients.

Figure 1.

(a) Inter-endothelial gaps, transcellular channels and tight junctions in endothelial cells. Scale bars are 500 nm in (1) and (3) 1 μm in (2). (b) Trans-endothelial pathways for nanoparticle uptake. Scale bars, 500 nm. (c) Zombie mouse model with only passive pathways for nanoparticle uptake. (d) Scheme showing OxPt/SN38 delivery by hitchhiking on LDL and LDLR-mediated endocytosis. (e) Anticancer efficacy of OxPt/SN38 with intratumorally injected 1 μg IgG or α-LDLR on MC38 tumor-bearing C57BL/6 mice. (f) Anticancer efficacy of OxPt/SN38 on WT and LDLR KO MC38 tumor-bearing C57BL/6 mice.

2.3. Receptor-mediated pathways

For systemically administered nanoparticles, it is very important to reduce the uptake by the MPS. As cationic surfaces increase nanoparticle–macrophage interactions and uptake[27], nanoparticles are typically coated with neutral polymers, such as polyethylene glycol (PEG), to extend their blood circulation time and increase their accumulation in tumors. The correlation between nanoparticle circulation half-life and density of PEG ligands was demonstrated by Perrault et al. [28].

Nanoparticles are sequestered by macrophages through phagocytosis, micropinocytosis, or receptor-mediated endocytic pathways[29]. Low-density lipoproteins and bacteria are taken up through scavenger receptors[30]. While these receptors may contribute to nanoparticle uptake, it is believed that more receptors may be involved in nanoparticle uptake due to the chemical and structural diversity of nanoparticles. Jiang et al.[31] recently showed that OxPt/SN38 nanoparticle containing oxaliplatin (OxPt) and cholesterol-conjugated SN38 prodrugs actively targets tumor by hitchhiking on low-density lipoprotein (LDL) particles and via LDL receptor (LDLR)-mediated endocytosis (Figure 1d), achieving 6.0- and 4.9-times higher tumor accumulations over free SN38 and OxPt, respectively. The anticancer efficacy of OxPt/SN38 was abrogated by LDLR blockade and in LDLR knockout mice (Figure 1e and f).

2.4. Protein coronas

When nanoparticles circulate in the blood, they will interact with serum materials to form a protein corona[32,33], which determines how the nanoparticles interact with innate immune systems and phagocytic cells[34]. Protein corona can also influence the physical stabilization and agglomeration of particles[35]. Walkey et al. studied protein coronas on different gold nanoparticles and found unique serum protein coating on each formulation using label-free liquid chromatography tandem mass spectrometry[27]. They further characterized the protein corona ‘fingerprints’ of 105 surface-modified gold nanoparticles and used the protein corona fingerprints to predict nanoparticle-cell associations[36]. The same group revealed that only proteins in the outer layer of the corona are responsible for binding to target proteins[37]. These findings illustrate the complexity of nanoparticle systems in blood circulation and suggest opportunities to tune plasma protein coatings to enhance nanoparticle uptake in tumors.

3. Platinum-based nanomedicines

Since the discovery of cisplatin’s ability to inhibit bacterial growth[38], thousands of platinum complexes have been synthesized and examined for their anticancer activities. To date, cisplatin, carboplatin and oxaliplatin remain the only clinically approved anticancer drugs worldwide[39,40]. Cisplatin is active against a wide spectrum of solid tumors but causes many severe side effects, including nephrotoxicity, hepatotoxicity, neurotoxicity, nausea, and vomiting. Many tumors are either intrinsically resistant or gradually acquire chemo-resistance[41]. With a slower hydration rate, carboplatin exhibits lower systemic toxicity than cisplatin but shows cross-resistance with cisplatin[42]. On the other hand, oxaliplatin does not show cross-resistance with cisplatin or carboplatin[43] and is particularly effective for gastrointestinal tumors.

Many platinum-based nanomedicines have been developed with the hope of increasing efficacy, reducing side effects, and overcoming drug resistance. Some have gone through clinic evaluations but none has been approved for clinical use[22]. Platinum-based nanoparticles containing combination chemotherapeutics and novel multiple synergistic therapies have also been developed.

3.1. Platinum-based monotherapy nanomedicines

A number of nanoparticle platforms, including polymer conjugates, micelles, liposomes, lipid particles, and nanoscale coordination polymer (NCP) particles, have been employed to deliver platinum drugs[43]. Among these nanoparticles, NCPs are of particular interest owing to the ability to deliver very high loadings of platinum drugs [44] and to have long circulation half-lives[45]. NCPs containing bisphosphate-derived cisplatin and oxaliplatin prodrugs showed blood circulation half-lives of 16.4±2.9 and 12.0±3.9 h, respectively, and 40-fold greater area under curves than free cisplatin and oxaliplatin[45]. By extending blood circulation have-lives, they took advantage of the EPR effect to effectively deliver platinum drugs to tumors and increase their antitumor efficacy over the parent drugs.

3.2. Platinum-based combination chemotherapy nanomedicines

As platinum drugs are typically used in combination with other chemotherapeutics[43], platinum-based combination chemotherapy nanomedicines can simultaneously enhance the delivery of multiple drugs to tumors to elicit synergistic antitumor effects[46]. Poon et al. reported the codelivery of oxaliplatin and gemcitabine monophosphate (GMP) by NCPs to simultaneously maximize therapeutic efficacy and minimize side effects[47]. A strong synergistic effect of oxaliplatin and GMP was observed in vitro against AsPc-1 and BxPc-3 pancreatic cancer cells. In the BxPc-3 model, the NCP showed higher anticancer potency than free oxaliplatin/gemcitabine combination and monotherapy NCPs. NCPs with carboplatin-bisphosphate and GMP showed prolonged blood circulation and improved tumor uptake, leading to 71% regression and 80% growth inhibition in SKOV-3 and A2780/CDDP tumor models, respectively [48].

Wang et al. [49] designed a combination nanoparticle (Pt(IV)–UA) via self-assembly of Pt(IV) prodrug of cisplatin, ursolic acid (UA), and PEG amphiphile for ovarian cancer treatment. UA is a weak aromatase inhibitor with an IC₅₀ of 32 μM. Pt(IV)–UA NPs overcame the detoxification and anti-apoptotic resistance of cancer cells by synergizing different anticancer mechanisms. In the A2780/CDPP tumor model, Pt(IV)–UA showed a higher survival rate (60%) than the monotherapy control (20%).

Jiang et al. [50] designed the OxPt/SN38 NCP with OxPt and cholesterol-conjugated SN38 prodrugs for simultaneous DNA crosslinking and topoisomerase I inhibition (Figure 2a). By targeting the LDLR, OxPt/SN38 significantly enhanced tumor accumulation of OxPt and SN38 to prolong mouse survival by 58–80 days over free drugs in three human colorectal cancer tumor models (Figure 2b)[31]. The two-stage SN38 release mechanism for OxPt/SN38 also alleviated hematological toxicity. OxPt/SN38 also significantly upregulated PD-L1 expression and, when combined with an anti-PD-L1 antibody (αPD-L1), activated the tumor immune microenvironment to elicit potent antitumor immunity, leading to regression of colorectal and pancreatic tumors with 33–50% cure rates (Figure 2c).

Figure 2.

(a) Scheme showing two-stage SN38 release strategy in OxPt/SN38 and its combination with immune checkpoint blockade. (b) tumor growth curves of human colorectal tumor models HT29, HCT116, and SW480 in nude mice after Q3D treatment with OxPt/SN38 NCP for up to 16 doses. (c) Tumor growth of MC38, CT26 and KPC mice tumors after combination treatment with OxPt/SN38 NCP and αPD-L1.

Guo et al. [51] used the nanoprecipitation technique to form Nano-Folox comprising dihydrate(1,2-diaminocyclohexane)Pt(II) and folinic acid. Nano-Folox enhanced blood circulation and tumor accumulation of drugs in tumors. Nano-Folox plus 5-fluorouracil elicited higher chemotherapeutic responses than combination treatments with folinic acid, 5-fluorouracil, and OxPt. When combined with αPD-L1, Nano-Folox plus 5-fluorouracil decreased liver metastases of colorectal cancer.

Tarannum et al. [52] used mesoporous silica nanoparticles (MSNs) to co-deliver gemcitabine and cisplatin for synergistic pancreatic ductal adenocarcinoma treatment (Figure 3a). The MSN particles were decorated with tumor-associated mucin1 specific antibody (TAB004) to afford TAB004-Gem-cisPt-MSN, which showed enhanced cell uptake and tumor accumulation over PEG-Gem-cisPt-MSN (Figure 3b). TAB004-Gem-cisPt-MSN had enhanced tumor inhibition (79%) compared to PEG-Gem-cisPt-MSNs (58%) and free drug groups (15%) (Figure 3c and d).

Figure 3.

(a) Scheme showing the fast release of gemcitabine and the delayed release of cisplatin from Gem-cisPt-MSNs. (b) Interaction between human tMUC1 on KCM cells and the TAB004 antibody on the MSN surface leads to higher cellular uptake. (c) Tumor growth curves of different treatments. (d) Tumor weights at the endpoint of the efficacy studies. PBS (purple), free Gem/cisPt (green), PEG-Gem-cisPt-MSNs (blue), and TAB004-Gem-cisPt-MSNs (red). (e) Scheme showing the sequential treatment schedule of Podo-NCP, CbP NCP and CD40 agonist. (f) Tumor growth inhibition of LL/2 tumor-bearing C57BL/6 mice. (g) Survival curves of LL/2 tumor-bearing C57BL/6 mice after Q4D × 4 sequential treatments.

3.3. Platinum-based synergistic anticancer combination nanomedicines

Combination nanomedicines containing both chemotherapeutics and noncytotoxic agents have the potential to enhance antitumor efficacy without increasing side effects. Combination nanomedicines with chemotherapeutics and small interfering RNAs (siRNAs) that silence multidrug-resistant (MDR) genes have been developed to overcome drug resistance whereas chemo-immunotherapeutic combination nanomedicines have been designed to overcome immune suppression.

He et al.[53] reported NCP particles containing cisplatin and gemcitabine in the core and MDR-targeting siRNAs in the shell (NCP/siRNAs) to overcome cisplatin resistance. Intraperitoneal injections of NCP/siRNAs effectively regressed/eradicated tumors in subcutaneous and intraperitoneal mouse models of cisplatin-resistant ovarian cancer. By silencing MDR genes in tumors, NCP/siRNAs enhanced the antitumor efficacy without causing side effects.

Ling et al.[54] reported the design of NCP particles for the co-delivery of carboplatin prodrug, digitoxin (Dig), and siRNA against PD-L1 (siPD-L1) for colorectal cancer and ovarian cancer treatment. Upon uptake by cancer cells and distribution in acidic organelles, the NCP particle rapidly released carboplatin for apoptosis, Dig for ICD and immune activation, and siPD-L1 for PD-L1 knockdown to realize highly effective chemo-immunotherapy. The NCP particle efficiently inhibited the growth and metastasis of advanced and aggressive cancers through the activation of innate and adaptive immune responses.

Ling et al.[55] reported the design of NCPs containing CbP (CbP-NP) or podophyllotoxin (Podo-NP) and their combination therapy with an anti-CD40 antibody (αCD40) for the treatment of transplanted and disseminated lung cancer in mouse models (Figure 3e). Podo-NP suppressed angiogenesis and normalized tumor vessels for efficient infiltration of NCP particles and immune cells. CbP-NP caused cell cycle arrest and induced tumor cell apoptosis. αCD40 activated antigen-presenting cells after being exposed to tumor-associated antigens and reversing immunosuppressive tumor microenvironments to recruit cytotoxic T cells. Sequential treatment with Podo-NP and CbP-NP followed by αCD40 inhibited tumor growth by 89.9 ± 1.3% and prolonged median survival by 56 days in LL/2 lung tumors (Figure 3f and g).

Liu et al.[56] designed a three-in-one NCP, OX/GC/CQ, consisting of oxaliplatin (OX), gemcitabine (GC), and 5-carboxy-8-hydroxyquinoline (CQ) prodrugs for triple chemo-immunotherapy (Figure 4a). CQ enhanced immunogenic cell death induced by OX/GC (Figure 4b) and downregulated PD-L1 expression to promote infiltration and activity of cytotoxic T lymphocytes. OX/GC/CQ reduced the growth of colorectal cancer and triple-negative breast cancer in mouse models, extending survival by 30–40 days over free drug controls (Figure 4c).

Figure 4.

(a) Scheme of OX/GC/CQ NCP. (b) CLSM images of CRT exposure (green) in MC38 cells after OX/GC/CQ NCP treatments; scale bars = 20 μm. (c) from left to right: averaged tumor weights of MC38 tumors, survival curves of s.c. CT26 tumor-bearing mice, and survival curves of orthotopic 4T1 tumor-bearing mice after OX/GC/CQ treatments.

4. Concluding remarks and perspectives

In this review, we discuss the role of the EPR effect on nanoparticle delivery to tumors and highlight the potential of leveraging our new understanding of nanoparticle uptake to further enhance drug delivery to tumors. As many platinum-based combination nanomedicines have shown an exciting ability to overcome drug resistance, reduce side effects, and enhance antitumor efficacy in preclinical studies, we provide our perspectives on the clinical potential of and key hurdles for their translation into the clinic.

First, the low success rate of cancer nanomedicines may be due to the less significant EPR effect in human tumors. Combination nanomedicines can simultaneously enhance the delivery of multiple drugs to exert more potent antitumor effects. Second, as platinum-based drugs have different physicochemical properties from other chemotherapeutics, new nanoparticle platforms are needed for the efficient co-delivery of platinum drugs and other chemotherapeutics. Third, reduced side effects of nanomedicines can be leveraged to improve patient survival by increasing drug doses or combining with chemotherapies. Fourth, the optimization of drug ratios in combination nanomedicines presents a significant challenge due to the differences between in vitro assays and in vivo outcomes in preclinical models, and more importantly, the differences between animal models and human patients. Lastly, the translation of combination nanomedicines may face significant regulatory hurdles due to the composition complexity and increased demands on toxicokinetic analysis. Despite these challenges, the exciting preclinical results of platinum-based combination nanomedicines provide a strong impetus for their clinical translation.