Nucleolin aptamer conjugated MSNPs-PLR-PEG multifunctional nanoconstructs for targeted co-delivery of anticancer drug and siRNA to counter drug resistance in TNBC

The emergence of drug resistance in cancer cells is among the major challenges for treating cancer. In the last few years, the co-delivery of drug and siRNA has shown promising results against drug-resistant cancers. In the present study, we developed mesoporous silica-based multifunctional nanocarrier for co-delivery against drug-resistant triple-negative breast cancer (TNBC) cells. We synthesized the nanocarrier by modifying mesoporous silica nanoparticles with poly-L-arginine, polyethylene glycol and AS1411 aptamer to impart siRNA binding ability, biocompatibility, and cancer cell specificity, respectively. We optimized the loading of doxorubicin (DOX) within the developed nanocarrier to avoid interference with siRNA binding. We ascertained the target specificity by performing a receptor blockade assay during cellular uptake studies. The cytotoxic efficacy of DOX and siRNA co-delivered using the developed nanocarrier was assessed using DOX-resistant MDA-MB-231 TNBC cells. The nanocarrier exhibited >10-fold and 40-fold reduction in the IC50 values of DOX due to co-delivery with BCl-xL and BCL-2 siRNA, respectively. The results were further validated using a 3-D in vitro cell culture system. This study demonstrates that the targeted co-delivery of drug and siRNA has a strong potential to overcome drug resistance in TNBC cells.