The pH-triggered polyglutamate brush co-delivery of MDR1 and survivin-targeting siRNAs efficiently overcomes multi-drug resistance of NSCLC

Abstract

Multi-drug resistance (MDR) is one of the major challenges in the successful chemotherapy of non-small cell lung cancer (NSCLC). Although RNA interference (RNAi) has been widely used to silence resistance-related genes, the effect remains unsatisfactory. In this study, we attempted to overcome MDR of NSCLC by simultaneously interfering with two RNAs that have different functions. A new pH-triggered polyglutamate brush polymer dimethylmaleic anhydride-poly(ethyleneglycol) monomethyl ether-b-polyglutamate-g-spermine (DMA-mPEG-b-PG-g-spermine, DPPGS) was designed and synthesized. The DPPGS/small interfering RNA (siRNA) complex nanoparticles (DPPGSN) were prepared. The results demonstrated that DPPGSN could be transformed from a negatively charged form into a positively charged form in the slightly acidic tumor extracellular environment. The siRNA targeting MDR1 mRNA (siMDR1) and siRNA targeting survivin mRNA (siSurvivin) could be efficiently co-delivered by DPPGS to simultaneously interfere with two genes (p < 0.01). Furthermore, DPPGS co-delivery of siMDR1 and siSurvivin lowered the IC₅₀ value of cisplatin (DDP) in A549/DDP (p < 0.01) cells and increased the apoptosis rate of the cells (p < 0.01). Therefore, co-delivery of siMDR1 and siSurvivin using DPPGS would be a promising approach for overcoming MDR of NSCLC.

Keywords:

• siRNA delivery
• multi-drug resistance
• MDR1
• survivin
• NSCLC

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This work was supported by the Joint Fund for Kunming Medical University and Yunnan Applied Basic Research [2018FE001(-086) and 2018FE001(-153)], the Open Foundation of the Key Laboratory of Tumor Immunotherapy in Yunnan Province [2017DG004-01], Kunming Science and Technology Plan Project [2019-1-N-25318000002911], Hospital Project of Yan'an Hospital Affiliated to Kunming Medical University [yyky016-002].