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

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 vari...

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Bibliographic Details
Published in:Chemical science (Cambridge) 2018-11, Vol.9 (43), p.8291-8306
Main Authors: Guégain, Elise, Tran, Johanna, Deguettes, Quentin, Nicolas, Julien
Format: Article
Language:English
Subjects:
Anticancer properties
Cancer
Chemical compounds
Chemical industry
Chemical Sciences
Chemical synthesis
Copolymerization
Copolymers
Cytotoxicity
Degradation
Drugs
Esters
Ethylene glycol
Life Sciences
Monomers
Nanoparticles
Parameters
Pharmaceutical sciences
Pharmacology
Polymers
Polymethyl methacrylate
Ring opening polymerization
Toxicity
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Summary: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.
ISSN:2041-6520
2041-6539
DOI:10.1039/c8sc02256a