Synthesis and selective cytotoxicity of a hyaluronic acid-antitumor bioconjugate.
A cell-targeted prodrug was developed for the anti-cancer drug Taxol, using hyaluronic acid (HA) as the drug carrier. HA-Taxol bioconjugates were synthesized by linking the Taxol 2'-OH via a succinate ester to adipic dihydrazide-modified HA (HA-ADH). The coupling of Taxol-NHS ester and HA-ADH provided several HA bioconjugates with different levels of ADH modification and different Taxol loadings. A fluorescent BODIPY-HA was also synthesized to illustrate cell targeting and uptake of chemically modified HA using confocal microscopy. HA-Taxol conjugates showed selective toxicity toward the human cancer cell lines (breast, colon, and ovarian) that are known to overexpress HA receptors, while no toxicity was observed toward a mouse fibroblast cell line at the same concentrations used with the cancer cells. The drug carrier HA-ADH was completely nontoxic. The selective cytotoxicity is consistent with the results from confocal microscopy, which demonstrated that BODIPY-HA only entered the cancer cell lines.
Luo
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Department of Medicinal Chemistry, The University of Utah, 30 South 2000 East, Room 201, Salt Lake City, Utah 84112-5820, USA.
Prestwich
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GD
D016475:3T3 Cells / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics / Q000633:toxicity*; D001896:Boron Compounds / Q000737:chemistry / Q000493:pharmacokinetics; D002240:Carbohydrate Sequence; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000378:metabolism; D004337:Drug Carriers; D004354:Drug Screening Assays, Antitumor; D005260:Female; D005456:Fluorescent Dyes / Q000737:chemistry / Q000493:pharmacokinetics; D006801:Humans; D006820:Hyaluronic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000633:toxicity*; D051379:Mice; D018613:Microscopy, Confocal; D008969:Molecular Sequence Data; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000378:metabolism; D017239:Paclitaxel / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000633:toxicity*; D011355:Prodrugs / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity*; D014407:Tumor Cells, Cultured
C095489:4,4-difluoro-4-bora-3a,4a-diaza-s-indacene; D000972:Antineoplastic Agents, Phytogenic; D001896:Boron Compounds; D004337:Drug Carriers; D005456:Fluorescent Dyes; D011355:Prodrugs; D006820:Hyaluronic Acid; D017239:Paclitaxel