Novel polymer micelle mediated co-delivery of doxorubicin and P-glycoprotein siRNA for reversal of multidrug resistance and synergistic tumor therapy.

Chun-Ge Zhang,Ji-Zhao Li,Shu-Di Yang,Zhi-Qiang Yuan,Wei-Liang Chen,Wen-Jing Zhu,Chun Liu,Yang Liu,Xue-Nong Zhang,Xiao-Feng Zhou

doi:10.1038/srep23859

Abstract

Co-delivery of chemotherapeutics and siRNA with different mechanisms in a single system is a promising strategy for effective cancer therapy with synergistic effects. In this study, a triblock copolymer micelle was prepared based on the polymer of N-succinyl chitosan–poly-L-lysine–palmitic acid (NSC–PLL–PA) to co-deliver doxorubicin (Dox) and siRNA–P-glycoprotein (P-gp) (Dox–siRNA-micelle). Dox–siRNA-micelle was unstable in pH 5.3 medium than in pH 7.4 medium, which corresponded with the in vitro rapid release of Dox and siRNA in acidic environments. The antitumor efficacy of Dox–siRNA-micelle in vitro significantly increased, especially in HepG2/ADM cells, which was due to the downregulation of P-gp. Moreover, almost all the Dox–siRNA-micelles accumulated in the tumor region beyond 24 h post-injection, and the co-delivery system significantly inhibited tumor growth with synergistic effects in vivo. This study demonstrated the effectiveness of Dox–siRNA-micelles in tumor-targeting and MDR reversal, and provided a promising strategy to develop a co-delivery system with synergistic effects for combined cancer therapy.

Highlights

Combination therapy and multidrug resistance (MDR) reversal are hot issues for improving therapeutic effects and reducing side effects[1,2,3,4]
We developed a co-delivery system based on the polymer of N-succinyl chitosan– PLL–palmitic acid (NSC–PLL–PA)
The size and surface morphology of micelles confirmed by transmission electron microscopy (TEM) (Fig. 2A) and atomic force microscopy (AFM) (Fig. 2B) showed that most of the micelle nanoparticles were compact and spherical, with an average diameter of approximately 170 nm

Summary

Introduction

Combination therapy and multidrug resistance (MDR) reversal are hot issues for improving therapeutic effects and reducing side effects[1,2,3,4]. Simultaneous co-delivery of chemotherapeutics and siRNA in a single vehicle in cancer chemotherapy is more effective than co-treatment with either chemotherapeutics or siRNA5–8. The clinical applications of chemotherapeutics are facing a series of challenges that hinder the effectiveness of chemotherapy, including insolubility (making them difficult to administer), non-targeting (causes insufficient penetration to tumors), and MDR (decreases intracellular accumulation)[15]. Short half-life in blood (rapidly degraded by nucleases), and poor cellular uptake (decreases intracellular accumulation); these limitations decrease the effectiveness of therapy[18,19,20]. PA, the hydrophobic core, was used to encapsulate Dox. The triblock polymer micelle co-delivering Dox and siRNA (Dox–siRNA-micelle) was designed to downregulate P-gp expression, overcome MDR, and exert synergistic therapeutic effects (Fig. 1). Cellular uptake and subcellular localization characteristics were investigated, and their tumor-targeting, antitumor, and antidrug-resistance properties were further confirmed

Methods

Results

Conclusion