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

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

  • Acta Biomater. 2022 Apr 15;143:320-332. doi: 10.1016/j.actbio.2022.02.033.
Qiang Luo 1,  Ling Lin 1,  Qiaorong Huang 1,  Zhenyu Duan 1,  Lei Gu 1,  Hu Zhang 2,  Zhongwei Gu 1,  Qiyong Gong 3,  Kui Luo 4
Affiliations

Affiliations

  • 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 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; Functional and Molecular Imaging Key Laboratory of Sichuan Province, and Research Unit of Psychoradiology, Chinese Academy of Medical Sciences, Chengdu 610041, China.
  • 4 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; Functional and Molecular Imaging Key Laboratory of Sichuan Province, and Research Unit of Psychoradiology, Chinese Academy of Medical Sciences, Chengdu 610041, China. Electronic address: luokui@scu.edu.cn.
PMID: 35235863 DOI: 10.1016/j.actbio.2022.02.033
Abstract

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.

Keywords

Anti-tumor; Biosafety; Brush copolymer poly(oligo-(ethylene glycol) methacrylate); Dendronized polymer; Dual-responsive prodrug.

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