3 years ago

Codelivery for Paclitaxel and Bcl-2 Conversion Gene by PHB-PDMAEMA Amphiphilic Cationic Copolymer for Effective Drug Resistant Cancer Therapy

Codelivery for Paclitaxel and Bcl-2 Conversion Gene by PHB-PDMAEMA Amphiphilic Cationic Copolymer for Effective Drug Resistant Cancer Therapy
Xian Jun Loh, Yun-Long Wu, Chuang Li, Sing Shy Liow, Cally Owh, Zibiao Li, Xiaoyuan Wang, Qiaoqiong Wu
Antiapoptotic Bcl-2 protein's upregulated expression is a key reason for drug resistance leading to failure of chemotherapy. In this report, a series of biocompatible amphiphilic cationic poly[(R)-3-hydroxybutyrate] (PHB)-b-poly(2-(dimethylamino)ethyl methacrylate) (PDMAEMA) copolymer, comprising hydrophobic PHB block and cationic PDMAEMA block, is designed to codeliver hydrophobic chemotherapeutic paclitaxel and Bcl-2 converting gene Nur77/ΔDBD with enhanced stability, due to the micelle formation by hydrophobic PHB segment. This copolymer shows less toxicity but similar gene transfection efficiency to polyethyenimine (25k). More importantly, this codelivery approach by PHB-PDMAEMA leads to increased drug resistant HepG2/Bcl-2 cancer cell death, by increased expression of Nur77 proteins in the Bcl-2 present intracellular mitochondria. This work signifies for the first time that cationic amphiphilic PHB-b-PDMAEMA copolymers can be utilized for the drug and gene codelivery to drug resistant cancer cells with high expression of antiapoptosis Bcl-2 protein and the positive results are encouraging for the further design of codelivery platforms for combating drug resistant cancer cells. A series of amphiphilic cationic poly[(R)-3-hydroxybutyrate]-b-poly(2-(dimethylamino)ethyl methacrylate) copolymers are designed as nonviral gene carrier with cationic micelle formation ability for hydrophobic drug encapsulation and enhanced stability. Furthermore, they are selected to codeliver chemotherapeutic paclitaxel and Bcl-2 conversion Nur77 gene in drug resistant HepG2/Bcl-2 cancer cells, which lead to increased Nur77 protein expression in intracellular mitochondria and drug resistant cancer cell death.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1002/mabi.201700186

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