Co-Delivery of Doxorubicin and Anti-BCL-2 siRNA by pH-Responsive Polymeric Vector to Overcome Drug Resistance in In Vitro and In Vivo HepG2 Hepatoma Model

Abstract

Drug resistance, developed through multiple mechanisms, is a major hindrance to successful chemotherapy of tumor. Combination therapy of chemotherapeutic drugs and siRNA represents an emerging strategy which may improve anticancer effect by synergistic actions. In this study, triblock copolymer of poly(ethylene glycol)- block-poly(l-lysine)- block-poly aspartyl ( N-( N', N'-diisopropylaminoethyl)) (PEG-PLL-PAsp(DIP)) was synthesized for the first time to enable the codelivery of BCL-2 siRNA and DOX. The system is supposed to not only bypass drug efflux but also down-regulate the antiapoptotic gene and consequently confronting against chemoresistance as well. Moreover, the pH responsive ability of the codelivery system can prevent drug leakage during circulation and guarantee swift drug release at tumors. The codelivered siRNA serves to suppress the expression of antiapoptotic BCL-2 and hence sensitize the cancer cells to anticancer drugs and produce improved therapeutic effect. Consequently, the codelivery of BCL-2 siRNA and anticancer drug DOX serves as a promising strategy against drug resistance in chemotherapy.

Liver-Targeted Combination Therapy Basing on Glycyrrhizic Acid-Modified DSPE-PEG-PEI Nanoparticles for Co-delivery of Doxorubicin and Bcl-2 siRNA

“…By contrast, the treatment of free DOX induced obvious intercellular vacuolation and dissolution of myocardial fibers, showing significant cardiotoxicity. This result suggested that the GH-DPP nanoparticles were biocompatible and useful for the delivery of chemotherapy drugs (Sun et al, 2018). Compared with nano-formulations for delivery DOX or siRNA alone, siRNA/DOX/GH-DPP nanoparticles showed stronger anti-tumor effect, indicating combination therapy could improve the anti-tumor efficiency by enhancing the sensitivity of cancer cells for chemotherapy drugs through inhibiting the expression of Bcl-2 protein (Chen et al, 2014).…”

“…By contrast, the drug release was slower at pH 7.4. The possible explanation is that the electrostatic interaction between positive segments (PEI) and negative segments (siRNA, GA-HA) is weak at lower pH value, leading to rapid release of the drug from the nano-carriers (Sun et al, 2018). Compared to siRNA/DOX/GH-DPP nanoparticles, the siRNA/DOX/DPP released more drugs at the same time.…”

“…Up-regulation of Bcl-2 expression was one of the mechanisms responsible for MDR, leading to the activation of anti-apoptotic pathways (Yin et al, 2014). The Bcl-2 siRNA, an antisense oligonucleotide sequence of Bcl-2, could silence the expression of Bcl-2 gene, resulting in cell apoptosis of liver cancer (Sun et al, 2018).…”

“…It is based on co-delivery nanoparticles system for combination of chemotherapeutics with other treatment approaches like RNAi (Zuckerman and Davis, 2015). The nanoparticles can simultaneously co-deliver two or more drugs to tumor region and thus improve the cancer therapeutic effect by synergistic/combined therapy effect, and reverse the multi-drug resistance (MDR) (Zhang et al, 2016; Sun et al, 2018).…”

Lipid and Polymer-Based Nanoparticle siRNA Delivery Systems for Cancer Therapy

“…Biodistribution analysis in HepG2/adriamycin (ADM) tumor-bearing mice showed that NP accumulation was observed at the tumor site 6 h after injection, and reached a maximum at 24 h, lasting for as long as 48 h. Furthermore, the treatment with DOX/siRNA-loaded PAD-PEG-PLL NPs was able to reduce tumor growth and increase the survival of tumor-bearing mice compared to controls. Lastly, ex-vivo analysis of the tumors showed reduced Bcl-2 and Ki67 expression after treatment, suggesting the induction of apoptosis and reduced cellular proliferation, which led to the control of tumor growth in the treated mice [72]. Another similar nanosystem was recently developed by Wang and colleagues incorporating a disulfide bridge between PEG and PLL (PEG-SS-PLL) to induce PEG release in the endosomes and facilitation of siRNA delivery to the cytoplasm of cancer cells.…”