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Conventionally, polycations are pharmacological inert used as nonviral gene delivery vectors with the sole function of compacting and protecting nucleic acids. Here, the first autophagy-inhibiting cationic polymer delivering plasmid DNA (pDNA) encoding TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) is prepared for cancer gene therapy. The copolymerization of methacryloyl chloroquine (MACQ) with 2-(dimethylamino)ethyl methacrylate (DMAEMA) not only improves transfection efficacy through hydrophobic modification, but also endows the copolymer with autophagy-blocking capability, which further sensitizes cancer cells to TRAIL induced apoptosis. Importantly, the designed copolymer shows efficient TRAIL expression, autophagy inhibition and enhances TRAIL-induced apoptosis in an autophagy-dependent manner. In contrast, TRAIL gene delivered by the autophagy-blocking-deficient control copolymer without the chlorine atom presents weaker antitumor efficacy, although expressing a similar amount of therapeutic TRAIL protein. Thus, this study demonstrates a conceptually new approach in which the therapeutic outcome of the delivered gene can be inherently strengthened by the delivery vehicle with intrinsic pharmacological activity. Copyright © 2020 Elsevier Ltd. All rights reserved.

Citation

Jiafeng Wang, Xuefei Zhou, Huifang Wang, Qian Xiao, Kefeng Ding, Xue Dong, Shufeng Xu, Bo Shen, Jihong Sun, Zhuxian Zhou, Jianbin Tang, Xiangrui Liu, Youqing Shen. Autophagy-inhibiting polymer as an effective nonviral cancer gene therapy vector with inherent apoptosis-sensitizing ability. Biomaterials. 2020 Oct;255:120156

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PMID: 32505754

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