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. (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.
Department of Biomedical Engineering, Virginia Commonwealth University, Richmond, Virginia 23284, United States.
Olga Yu
OY
Zolotarskaya
Alison F
AF
Wagner
Jason M
JM
Beckta
Kristoffer
K
Valerie
Kenneth J
KJ
Wynne
Hu
H
Yang
D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry* / Q000378:metabolism; D001932:Brain Neoplasms / Q000188:drug therapy / Q000473:pathology*; D002166:Camptothecin / Q000737:chemistry* / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D057930:Click Chemistry; D005910:Glioma / Q000188:drug therapy / Q000473:pathology*; D006801:Humans; D008156:Luciferases / Q000378:metabolism; D015394:Molecular Structure; D011092:Polyethylene Glycols / Q000737:chemistry / Q000378:metabolism; D011108:Polymers / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D011409:Propylene Glycols / Q000737:chemistry* / Q000378:metabolism; D012995:Solubility; D014407:Tumor Cells, Cultured; D014867:Water / Q000737:chemistry
D000972:Antineoplastic Agents, Phytogenic; D011108:Polymers; D011409:Propylene Glycols; C524812:poly(oxetane); D014867:Water; D011092:Polyethylene Glycols; D008156:Luciferases; D002166:Camptothecin