Synthesis of Water-Soluble Camptothecin-Polyoxetane Conjugates via Click Chemistry

Abstract

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.

Department(s)

Chemical and Biochemical Engineering

Keywords and Phrases

anticancer drug delivery; brush polymer; glioma; nanomedicine; polymer-drug conjugates; polyoxetane

International Standard Serial Number (ISSN)

1543-8384; 1543-8392

Document Type

Article - Journal

Document Version

Citation

File Type

text

Language(s)

English

Rights

© 2012 American Chemical Society (ACS), All rights reserved.

Publication Date

05 Nov 2012

PubMed ID

23051100

Link to Full Text

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