Peptide-Based Autophagic Gene and Cisplatin Co-delivery Systems Enable Improved Chemotherapy Resistance
journal contributionposted on 2019-03-29, 00:00 authored by Yao-Xin Lin, Yi Wang, Hong-Wei An, Baowen Qi, Junqing Wang, Lei Wang, Jinjun Shi, Lin Mei, Hao Wang
Cisplatin-based chemotherapy is a widely used first-line strategy for numerous cancers. However, drug resistances are often inevitable accompanied by the long-term use of cisplatin in vivo, significantly hampering its therapeutic efficacy and clinical outcomes. Among others, autophagy induction is one of the most common causes of tumor resistance to cisplatin. Herein, a self-assembled nanoprodrug platform was developed with the synergistic effect of cisplatin and RNAi to fight against cisplatin-resistant lung cancer. The nanoprodrug platform consists of three molecular modules, including prodrug complex of Pt(IV)-peptide-bis(pyrene), DSPE-PEG, and cRGD-modified DSPE-PEG. The Pt(IV) is immobilized with peptide via amide bonds, allowing the Pt(IV) to be loaded with a loading efficiency of >95% and rapid-release active platinum ions (Pt(II)) in the presence of glutathione (GSH). Meanwhile, the peptide of the prodrug complex could efficiently deliver Beclin1 siRNA (Beclin1 is an autophagy initiation factor) to the cytoplasm, thereby leading to autophagy inhibition. In addition, incorporation of DSPE-PEG and cRGD-modified DSPE-PEG molecules improves the biocompatibility and cellular uptake of the nanoprodrug platform. In vivo results also indicate that the nanoprodrug platform significantly inhibits the growth of a cisplatin-resistant tumor on xenograft mice models with a remarkable inhibition rate, up to 84% after intravenous injection.
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resistanceGSHxenograft mice modelsCisplatin Co-delivery Systems EnablepeptideinhibitionPtBeclin 1 siRNAtumorself-assembled nanoprodrug platformcRGD-modified DSPE-PEG moleculesvivoautophagy initiation factorcisplatin-resistant lung cancerPeptide-Based Autophagic GeneChemotherapy Resistance Cisplatin-based chemotherapynanoprodrug platform