Dual-Responsive Mesoporous Silica Nanoparticles Mediated Codelivery of Doxorubicin and Bcl-2 SiRNA for Targeted Treatment of Breast Cancer

Abstract

The combination of chemotherapy and gene therapy could induce the enhanced therapeutic efficacy in the cancer therapy. To achieve this goal, a new mesoporous silica nanoparticles (MSNs)-based codelivery system was developed for targeted simultaneous delivery of doxorubicin (DOX) and Bcl-2 small interfering RNA (siRNA) into breast cancer cells. The multifunctional MSNs (MSNs-PPPFA) were prepared by modification of polyethylenimine–polylysine copolymers (PEI-PLL) via the disulfide bonds, to which a targeting ligand folate-linked poly(ethylene glycol) (FA-PEG) was conjugated. The multifunctional MSNs-PPPFA nanocarrier has the ability to encapsulate DOX into the mesoporous channels of MSNs, while simultaneously carrying siRNA via electrostatic interaction between cationic MSNs-PPPFA and anionic siRNA. The resulting MSNs-PPPFA nanoparticles were characterized with various techniques. The drug release results reveal that DOX released from DOX-loaded MSNs-PPPFA are both pH- and redox-responsive, and the results of cell viability and hemolysis assays show that the functional nanocarrier has excellent biocompatibility. Importantly, the folate-conjugated MSNs-PPPFA showed significantly enhanced intracellular uptake in the folate receptor overexpressed MDA-MB-231 breast cancer cells than nontargeted counterparts and thus results in more DOX and siRNA being codelivered into the cells. Furthermore, the delivery of Bcl-2 siRNA obviously downregulate the Bcl-2 protein expression, and thus targeted codelivery of DOX and Bcl-2 siRNA by DOX@MSNs-PPPFA/Bcl-2 siRNA in MDA-MB-231 cells could induce remarkable cell apoptosis as indicated by the results of cell viability and cell apoptosis assays. These results indicate that the constructed DOX@MSNs-PPPFA/Bcl-2 siRNA codelivery system is promising for targeted treatment of breast cancer.