Synthesis of Water-Soluble Camptothecin-Polyoxetane Conjugates via Click Chemistry
Water-soluble camptothecin (CPT)-polyoxetane conjugates were synthesized using a clickable polymeric platform P(EAMO) that was made by polymerization of acetylene-functionalized 3-ethyl-3-(hydroxymethyl)oxetane (i.e., EAMO). CPT was first modified with a linker 6-azidohexanoic acid via an ester linkage to yield CPT-azide. CPT-azide was then click coupled to P(EAMO) in dichloromethane using bromotris(triphenylphosphine)copper(I)/N,N-diisopropylethylamine. For water solubility and cytocompatibility improvement, methoxypolyethylene glycol azide (mPEG-azide) was synthesized from mPEG 750 g mol-1 and click grafted using copper(II) sulfate and sodium ascorbate to P(EAMO)-g-CPT. 1H NMR spectroscopy confirmed synthesis of all intermediates and the final product P(EAMO)-g-CPT/PEG. CPT was found to retain its therapeutically active lactone form. The resulting P(EAMO)-g-CPT/PEG conjugates were water-soluble and produced dose-dependent cytotoxicity to human glioma cells and increased γ-H2AX foci formation, indicating extensive cell cycle-dependent DNA damage. Altogether, we have synthesized CPT-polymer conjugates able to induce controlled toxicity to human cancer cells.
O. Y. Zolotarskaya et al., "Synthesis of Water-Soluble Camptothecin-Polyoxetane Conjugates via Click Chemistry," Molecular Pharmaceutics, vol. 9, no. 11, pp. 3403 - 3408, American Chemical Society (ACS), Nov 2012.
The definitive version is available at https://doi.org/10.1021/mp3005066
Chemical and Biochemical Engineering
Keywords and Phrases
anticancer drug delivery; brush polymer; glioma; nanomedicine; polymer-drug conjugates; polyoxetane
International Standard Serial Number (ISSN)
Article - Journal
© 2012 American Chemical Society (ACS), All rights reserved.
05 Nov 2012