Polymeric Nanoparticle Delivery of Combination Therapy with Synergistic Effects in Ovarian Cancer

Abstract

Treatment of ovarian cancer is challenging due to late stage diagnosis, acquired drug resistance mechanisms, and systemic toxicity of chemotherapeutic agents. Combination chemotherapy has the potential to enhance treatment efficacy by activation of multiple downstream pathways to overcome drug resistance and reducing required dosages. Sequence of delivery and the dosing schedule can further enhance treatment efficacy. Formulation of drug combinations into nanoparticles can further enhance treatment efficacy. Due to their versatility, polymer-based nanoparticles are an especially promising tool for clinical translation of combination therapies with tunable dosing schedules. We review polymer nanoparticle (e.g., micelles, dendrimers, and lipid nanoparticles) carriers of drug combinations formulated to treat ovarian cancer. In particular, the focus on this review is combinations of platinum and taxane agents (commonly used first line treatments for ovarian cancer) combined with other small molecule therapeutic agents. In vitro and in vivo drug potency are discussed with a focus on quantifiable synergistic effects. The effect of drug sequence and dosing schedule is examined. Computational approaches as a tool to predict synergistic drug combinations and dosing schedules as a tool for future nanoparticle design are also briefly discussed.

Keywords: cancer; combination chemotherapy; drug delivery; nanocarrier; ovarian carcinoma; polymer; synergy; therapeutic efficacy.

Figure 6

(A) Schematic overview of co-delivery of cisplatin and gemcitabine using polymer nanocarriers for synergistic effect (adapted with permission from [30] MDPI Open Access). (B) Co-formulation of cisplatin (CIS) and talazoparib (BMN) or olaparib (AZD) in lipid/polymeric nanoparticles (NPs) enhanced potency as indicated by the decrease in IC50 compared to the free drug (FD). * indicate a statistically significant difference between the IC50 of the free drug and nanoparticle formulation. Statistical analysis was performed by one-way ANOVA (p < 0.05). Reprinted (adapted) from [101] John Wiley & Sons Open Access. (C) Paclitaxel and tanespimycin (17-AAG) co-delivered in micelles (green) displayed the greatest suppression in tumor growth as indicated by the statistically significant reduced tumor weight on day 43 compared to the free drug combination (*, p < 0.05; ***, p < 0.0005, n = 6 mice). Reprinted (adapted) with permission from [112] PLoS Open Access.

Figure 1

(A) Overview of mechanisms affecting cancer cell resistance to anticancer therapy ranging from changing protein expression to effecting drug accumulation, drug metabolism, to repair of apoptotic pathways. (B) Advantages of drug combination for treating ovarian cancer. Synergy can be observed when the drug combinations act through multiple pathways. Combinations can overcome multi-drug resistance (MDR) mechanisms to increase anticancer activity. Delivery of drug combinations can also reduce toxicity by reducing the required doses of each drug.

Figure 2

(A) Isobologram to visualize effect of combining drug A and B. The line between the IC50 of drug A and B indicates an additive effect. Below the line of additivity indicates synergistic drug interactions; above the line of additivity indicates antagonistic drug interactions. (B) Visual representation the combination index (CI) versus fraction affected (f_A) Figure adapted from [37], Copyright © 2012 Breitinger. Licensee IntechOpen.

Figure 3

(A) Dose-response curve shows sequence-dependent response of sequentially delivering a platinum drug, ZD0473 and paclitaxel in in platinum resistant cells, A2780cis. The results show that delivering platinum drug followed by paclitaxel exhibits greater reduction in cell growth. Reprinted from [45], Copyright 2002, with permission from Elsevier. (B) Combination index analysis of cisplatin and a RTK inhibitor, GW282974A (GW), comparing PEO1 and platinum-resistant cells, PEO1CarboR cells showing synergy (CI < 1) depends on drug concentration and cell type Reprinted from [46], Copyright 2006, with permission from Elsevier. (C) Overview of enhanced apoptosis in ovarian cancer cells due to combination treatment of scutellarin and cisplatin. Specifically, the combination treatment increases the ability of cisplatin to bind to DNA resulting in increased the level of cleaved capsase-3 and increased the ratio of Bax/Bcl-2 which promote apoptosis. Overall the result of the drug combination is synergistic (CI 0.566–0.796 depending on drug ratio) Reprinted from [47]. Copyright 2019, with permission from Elsevier.

Figure 4

Schematic overview of the polymer-based nanocarriers used for combination therapy in ovarian cancer included in this review.

Figure 5

(A) Dual drug loaded polymer micelle loaded with chetomin (CHE) and everolimus (EVR) in the core. (B) The dual drug loaded micelles is synergistic compared to the single drug loaded micelles for TOV21G and ES2 cells in vitro (CI < 1). (C) The dual drug loaded micelles are more effective at reducing tumor volume compared to the single drug loaded micelles in an ES2 xenograft model. * Represents significant difference from control (saline), δ represents significant difference from dual drug loaded micelles evaluated using one way ANOVA with Tukey’s Multiple Comparison Test (compare all pairs of columns) using a significant level (α) of 0.05, n = 4. Adapted from [98]. Copyright 2019, with permission from Elsevier.

Figure 7

Combination index of (A) SKOV-3 and (B) ES-2 cells treated with telodendrimer nanocarriers loaded with paclitaxel and cisplatin (CDDP) at different ratio. The telodendrimers produce different drug interaction due to drug ratio and cell type. Reprinted from [119], Copyright 2015, with permission from Elsevier. (C) Schematic of polyamidoamine (PAMA) dendrimer formulated with hyaluronic acid (HA) loaded with cisplatin (Pt) and doxorubicin (Dox). (D) In vivo co-delivery of cisplatin with doxorubicin in polyamidoamine dendrimers enhance drug accumulation in tumor tissue facilitated by hyaluronic acid targeting ligands. (a: saline; b: Cy7.5-labeled PAMAM; c: Cy7.5-labeled HA@PAMAM). Reprinted from [120], Copyright 2019, with permission from Elsevier.