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Peptide-Based Autophagic Gene and Cisplatin Co-delivery Systems Enable Improved Chemotherapy Resistance
journal contribution
posted 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 WangCisplatin-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