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Degradable polymer prodrugs with adjustable activity from drug-initiated radical ring-opening copolymerization

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Abstract

Degradable polymer prodrugs based on gemcitabine (Gem) as an anticancer drug were synthesized by ‘drug-initiated’ nitroxide-mediated radical ring-opening copolymerization (NMrROP) of methacrylic esters and 2-methylene-4-phenyl-1,3-dioxolane (MPDL). Different structural parameters were varied to determine the best biological performances: the nature of the monomer [i.e., oligo(ethylene glycol) methacrylate (OEGMA) or methyl methacrylate (MMA)], the nature of the Gem-polymer linker (i.e., amide or amide and diglycolate) and the MPDL content in the copolymer. Depending on the nature of the methacrylate monomer, two small libraries of water-soluble copolymer prodrugs and nanoparticles were obtained (Mn ∼10 000 g mol−1, Đ = 1.1–1.5), which exhibited tunable hydrolytic degradation under accelerated conditions governed by the MPDL content. Drug-release profiles in human serum and in vitro anticancer activity on different cell lines enabled preliminary structure–activity relationships to be established. The cytotoxicity was independently governed by: (i) the MPDL content – the lower the MPDL content, the greater the cytotoxicity; (ii) the nature of the linker – the presence of a labile diglycolate linker enabled a greater Gem release compared to a simple amide bond and (iii) the hydrophilicity of the methacrylate monomer–OEGMA enabled a greater anticancer activity to be obtained compared to MMA-based polymer prodrugs. Remarkably, the optimal structural parameters enabled reaching the cytotoxic activity of the parent (free) drug.

Graphical abstract: Degradable polymer prodrugs with adjustable activity from drug-initiated radical ring-opening copolymerization

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Publication details

The article was received on 22 May 2018, accepted on 28 Aug 2018 and first published on 13 Sep 2018


Article type: Edge Article
DOI: 10.1039/C8SC02256A
Citation: Chem. Sci., 2018, Advance Article
  • Open access: Creative Commons BY-NC license
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    Degradable polymer prodrugs with adjustable activity from drug-initiated radical ring-opening copolymerization

    E. Guégain, J. Tran, Q. Deguettes and J. Nicolas, Chem. Sci., 2018, Advance Article , DOI: 10.1039/C8SC02256A

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