Synthesis of Water-Soluble Camptothecin鈥揚olyoxetane Conjugates via Click Chemistry

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• 作者：Olga Yu. Zolotarskaya ; Alison F. Wagner ; Jason M. Beckta ; Kristoffer Valerie ; Kenneth J. Wynne ; Hu Yang
• 刊名：Molecular Pharmaceutics
• 出版年：2012
• 出版时间：November 5, 2012
• 年：2012
• 卷：9
• 期：11
• 页码：3403-3408
• 全文大小：358K
• 年卷期：v.9,no.11(November 5, 2012)
• ISSN：1543-8392

文摘

Water-soluble camptothecin (CPT)鈥損olyoxetane 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^鈥? 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 纬-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.

Keywords:

glioma; nanomedicine; brush polymer; polymer鈭抎rug conjugates; anticancer drug delivery; polyoxetane