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

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

Chem Sci

Institut Galien Paris-Sud , CNRS UMR 8612 , Univ Paris-Sud , Faculté de Pharmacie , 5 rue Jean-Baptiste Clément, 92290 Châtenay-Malabry , France . Email: ; Tel: +33 1 46 83 58 53 ; www.twitter.com/julnicolas.

Published: November 2018

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 [, oligo(ethylene glycol) methacrylate (OEGMA) or methyl methacrylate (MMA)], the nature of the Gem-polymer linker (, 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 ( ∼10 000 g mol, = 1.1-1.5), which exhibited tunable hydrolytic degradation under accelerated conditions governed by the MPDL content. Drug-release profiles in human serum and 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.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6240899PMC
http://dx.doi.org/10.1039/c8sc02256aDOI Listing

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