A hyaluronic acid-taxol antitumor bioconjugate targeted to cancer cells

被引:226
作者
Luo, Y
Ziebell, MR
Prestwich, GD
机构
[1] Univ Utah, Dept Med Chem, Salt Lake City, UT 84112 USA
[2] SUNY Stony Brook, Dept Physiol & Biophys, Stony Brook, NY 11794 USA
关键词
D O I
10.1021/bm000283n
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
A cell-targeted polymeric prodrug prepared from Taxol and chemically modified hyaluronic acid (HA) was evaluated in vitro. Herein we report four results in support of the selective uptake and targeted toxicity of the HA-Taxol prodrug. First, a fluorescently labeled HA-Taxol (FITC-HA-Taxol) was synthesized and used to demonstrate cell-specific binding and uptake using flow cytometry and confocal microscopy. Second, the selective cytotoxicity of FITC-HA-Taxol allowed direct correlation of uptake with selective cytotoxicity. Third, the rapid uptake and selective cytotoxicity of HA-Taxol bioconjugates could be blocked by either excess HA or by an anti-CD44 antibody, but not by chondroitin sulfate (CS), Finally, the release of free Taxol From HA-Taxol in human plasma or in cell culture media revealed that the free drug was hydrolytically released from the bioconjugate by cleavage of the labile 2' ester linkage. Taken together, these data support the notion that the targeted cytotoxicity of HA-Taxol bioconjugates requires receptor-mediated cellular uptake of the bioconjugate followed by hydrolytic release of free Taxol.
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页码:208 / 218
页数:11
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