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Autophagy-inhibiting polymer as an effective nonviral cancer gene therapy vector with inherent apoptosis-sensitizing ability.
Metadata
Journalbiomaterials10.317Date
2020 May 31
4 months ago
Type
Journal Article
Volume
2020-Oct / 255 : 120156
Author
Wang J 1, Zhou X 1, Wang H 1, Xiao Q 2, Ding K 3, Dong X 4, Xu S 4, Shen B 4, Sun J 5, Zhou Z 1, Tang J 1, Liu X 6, Shen Y 1
Affiliation
  • 2. Department of Colorectal Surgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, 310009, China; Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Key Laboratory of Molecular Biology in Medical Sciences, Zhejiang Province, China; The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, 310009, China.
  • 3. Department of Colorectal Surgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, 310009, China; Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Key Laboratory of Molecular Biology in Medical Sciences, Zhejiang Province, China; The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, 310009, China. Electronic address: [email protected]
  • 4. Department of Radiology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, China.
  • 5. Department of Radiology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, China. Electronic address: [email protected]
  • 6. Key Laboratory of Biomass Chemical Engineering of Ministry of Education and Center for Bionanoengineering, College of Chemical and Biological Engineering, Zhejiang University, Hangzhou, 310027, China; Department of Radiology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, China. Electronic address: [email protected]
Doi
PMIDMESH
Abstract
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.
Keywords: Apoptosis sensitizing Autophagy inhibition Cancer therapy Gene delivery Polycation
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10.3
Biomaterialsbiomaterials
Metadata
LocationNetherlands
FromELSEVIER SCI LTD

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