摘要
The combination of chemotherapy and gene therapy is a versatile strategy for treating multi-drug-resistant cancer. Accordingly, we developed a pH-responsive triblock copolymeric carrier for delivering chemotherapeutic and genetic drugs simultaneously. We synthesized a series of block and random copolymers with the same monomer composition, namely poly(ethylene glycol)-b-poly(2-(dimethylamino)ethyl methacrylate)-b-poly(2-(diisopropylamino)ethyl methacrylate) (PEG-b-PDMAEMA-b-PDPA) and poly(ethylene glycol)-b-poly[(2-(dimethylamino)ethyl methacrylate)-r-(2-(diisopropylamino)ethyl methacrylate)] (PEG-b-(PDMAEMA-r-PDPA)), by using atom transfer radical polymerization (ATRP) and then used them to encapsulate and release doxorubicin (Dox) and Bcl-2 siRNA. Compared with the random copolymers, the block copolymers exhibited a higher Dox-loading efficiency and Dox-loading capacity and higher Bcl-2 siRNA condensation efficiency. The siRNA condensation efficiency could be increased by increasing the length of the PDMAEMA segment in either the block copolymers or random copolymers. PEG-b-PDMAEMA-b-PDPA encapsulated Dox and Bcl-2 siRNA to form Dox/Bcl-2 siRNA-loaded micelleplexes with 87% and 90% loading efficiency, respectively. Changing the pH value from 7.4 to 5.0 engendered a burst release of Dox and Bcl-2 siRNA from the Dox/Bcl-2 siRNA-loaded micelleplexes, thus enhancing the cumulative release efficiency of Dox from 24% to 69% and that of Bcl-2 siRNA from 15% to 59% within 24 h. Our in vitro study revealed that the Dox/Bcl-2 siRNA-loaded micelleplexes downregulated Bcl-2 mRNA expression (51% expression) and further inhibited antiapoptotic mechanisms to sensitize drug-resistant triple-negative breast cancer (TNBC) cells to Dox (36% cell viability); this thus demonstrates the benefits of combining chemotherapy and gene therapy.