A hyaluronic acid-taxol antitumor bioconjugate targeted to cancer cells.
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.
Luo
Y
Y
Department of Medicinal Chemistry, University of Utah, Salt Lake City, Utah 84112-5820, USA.
Ziebell
M R
MR
Prestwich
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GD
D016475:3T3 Cells; D000818:Animals; D019138:Antibodies, Blocking / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage* / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D002807:Chondroitin / Q000494:pharmacology; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D018960:Hyaluronan Receptors / Q000276:immunology; D006820:Hyaluronic Acid / Q000737:chemistry*; D007202:Indicators and Reagents; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D018613:Microscopy, Confocal; D008970:Molecular Weight; D017239:Paclitaxel / Q000008:administration & dosage* / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D011355:Prodrugs / Q000008:administration & dosage* / Q000494:pharmacology; D013056:Spectrophotometry, Ultraviolet; D014407:Tumor Cells, Cultured
D019138:Antibodies, Blocking; D000972:Antineoplastic Agents, Phytogenic; D018960:Hyaluronan Receptors; D007202:Indicators and Reagents; D011355:Prodrugs; D006820:Hyaluronic Acid; D002807:Chondroitin; D017239:Paclitaxel