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Dual stimuli-responsive dendronized prodrug derived from poly(oligo-(ethylene glycol) methacrylate)-based copolymers for enhanced anti-cancer therapeutic effect.

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机构: [1]Huaxi MR Research Center (HMRRC), Regenerative Medicine Research Center, Laboratory of Stem Cell Biology, Department of Radiology, National Clinical Research Center for Geriatrics, Frontiers Science Center for Disease-related Molecular Network, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China [2]Amgen Bioprocessing Centre, Keck Graduate Institute, Claremont, CA 91711, USA [3]Functional and Molecular Imaging Key Laboratory of Sichuan Province, and Research Unit of Psychoradiology, Chinese Academy of Medical Sciences, Chengdu 610041, China
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In this study, we developed an enzyme- and pH-responsive dendronized poly(oligo-(ethylene glycol) methacrylate) (pOEGMA)-doxorubicin (DOX) polymeric prodrug, which combined the pOEGMA structure with a degradable peptide dendron. The introduction of the dendron in the prodrug hindered the entanglement of brush oligo-(ethylene glycol) (OEG) chains, allowed the prodrug to possess dual stimuli-responsiveness, and mediated self-assembly of the polymeric prodrug to form stable nanoparticles (NPs). Brush conformation of polyethylene glycol (PEG) side chains endowed the NPs with long-term circulation with a half-life of 16.0 h. The dual-responsive dendritic structure enhanced cellular uptake of NPs and facilitated drug release in response to overexpressed cathepsin B and an acidic pH in the tumor microenvironment, resulting in an enhanced therapeutic effect with a tumor inhibition rate of 72.9% for 4T1 tumor-bearing mice. The NPs were demonstrated to possess great hemocompatibility and biosafety. Therefore, this strategy could provide great insight for the design of poly(oligo-(ethylene glycol) methacrylate)-based copolymers as drug delivery carriers. STATEMENT OF SIGNIFICANCE: We propose a dual-stimuli-responsive dendronized strategy for improving the cancer therapeutic effect of the poly(oligo-(ethylene glycol) methacrylate) (pOEGMA)-based drug conjugates. The introduction of the functional dendron promotes self-assembly of the polymeric prodrug into nanoparticles, hindering the entanglement of brush oligo-(ethylene glycol) (OEG) chains in the conjugated drugs. The obtained poly OEGMA-GFLG-Dendron-NH-N=DOX nanoparticles maintains long circulation, while addresses the drug release issue due to the presence of high-density PEG. The drug delivery system exhibits a high therapeutic potentcy with negligible side effects.Copyright © 2022. Published by Elsevier Ltd.

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出版当年[2022]版:
大类 | 1 区 工程技术
小类 | 1 区 材料科学:生物材料 1 区 工程:生物医学
最新[2023]版:
大类 | 1 区 医学
小类 | 1 区 工程:生物医学 1 区 材料科学:生物材料
第一作者:
第一作者机构: [1]Huaxi MR Research Center (HMRRC), Regenerative Medicine Research Center, Laboratory of Stem Cell Biology, Department of Radiology, National Clinical Research Center for Geriatrics, Frontiers Science Center for Disease-related Molecular Network, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
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通讯机构: [1]Huaxi MR Research Center (HMRRC), Regenerative Medicine Research Center, Laboratory of Stem Cell Biology, Department of Radiology, National Clinical Research Center for Geriatrics, Frontiers Science Center for Disease-related Molecular Network, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China [3]Functional and Molecular Imaging Key Laboratory of Sichuan Province, and Research Unit of Psychoradiology, Chinese Academy of Medical Sciences, Chengdu 610041, China [*1]Huaxi MR Research Center (HMRRC), Regenerative Medicine Research Center, Laboratory of Stem Cell Biology, Department of Radiology, National Clinical Research Center for Geriatrics, Frontiers Science Center for Disease-related Molecular Network, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.
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