Co-delivery of autophagy inhibitor ATG7 siRNA and docetaxel for breast cancer treatment

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Abstract

The lysosomal degradation pathway of autophagy has a crucial role in protecting cancer cells from multiple endogenous and exogenous stresses, particularly during the pathogenesis of cancer. Accordingly, agents that inhibit autophagy may have broad therapeutic applications. We have developed a novel strategy based on co-delivery of an autophagy related 7 (ATG7) siRNA and docetaxel (DTX) in a crosslinked, reducible, peptide-based micellar system for breast cancer treatment. Our results show that DTX and siATG7 co-treatment exhibited 2.5- and 1.7-fold higher cytotoxicity and apoptosis, respectively, in MCF-7 cells than DTX treatment alone did, which demonstrates that siATG7 enhances the efficacy and apoptotic effect of DTX. Our study showed that breast cancer cell lines differ greatly in their dependency on autophagy under conditions of normal or stress. Furthermore, siATG7 delivery in a micellar system can effectively silence the ATG7 gene, suppress DTX-induced autophagy, and exhibit improved anticancer effects. In addition, DTX in a co-delivery system showed at least a 1.84-fold greater tumor inhibition compared to that of DTX-loaded micelles in vivo. Finally, a Cy5 indicator that was loaded into crosslinked micelles revealed a remarkably high accumulation in tumors, demonstrating excellent tumor targeting ability of the micellar system. Therefore, our research demonstrated the synergistic efficacy of the combination of autophagy inhibition and chemotherapy delivered by polypeptide micelles for breast cancer therapy.

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