Synthesis of water-soluble camptothecin-polyoxetane conjugates via click chemistry. Mol Pharm 2012 Nov 05;9(11):3403-8
Date
10/12/2012Pubmed ID
23051100Pubmed Central ID
PMC3496795DOI
10.1021/mp3005066Scopus ID
2-s2.0-84868524364 (requires institutional sign-in at Scopus site) 27 CitationsAbstract
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. (1)H 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.
Author List
Zolotarskaya OY, Wagner AF, Beckta JM, Valerie K, Wynne KJ, Yang HAuthor
Hu Yang PhD Chair, Professor in the Biomedical Engineering department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
Antineoplastic Agents, PhytogenicBrain Neoplasms
Camptothecin
Cell Survival
Click Chemistry
Glioma
Humans
Luciferases
Molecular Structure
Polyethylene Glycols
Polymers
Propylene Glycols
Solubility
Tumor Cells, Cultured
Water
