title: Paclitaxel derivatives for targeted therapy of cancer: toward the development of smart taxanes.
abstract: The pharmacologic efficacy of the promising antitumor agent paclitaxel (Taxol) may be potentially enhanced through derivatization of the drug to a water-soluble tumor-recognizing conjugate. This work reports the design and synthesis of the first tumor-directed derivative of paclitaxel. A 7-amino acid synthetic peptide, BBN[7-13], which binds to the cell surface bombesin/gastrin-releasing peptide (BBN/GRP) receptor, was conjugated to the paclitaxel-2'-hydroxy function by a heterobifunctional poly(ethylene glycol) linker. The resulting conjugate, designated PTXPEGBBN[7-13], was soluble to the upper limit of tested concentrations (250 mg/mL). The conjugate completely retained the receptor binding properties of the attached peptide as compared with those of the unconjugated BBN[7-13]. In experiments with NCI-H1299 human nonsmall cell lung cancer cells, the cytotoxicity of the PTXPEGBBN[7-13] conjugate at a 15 nM dose was enhanced by a factor of 17.3 for 24 h and 10 for 96 h exposure times, relative to paclitaxel. The IC(50) of the conjugate, tested against the same cell line, was lower than the free drug by a factor of 2.5 for both 24 h and 96 h exposures. These results describe, for the first time, the design and synthesis of a soluble tumor-directed paclitaxel prodrug which may establish a new mode for the utilization of this drug in cancer therapy.
authors.affiliation: Departments of Radiation Oncology and Medicine, and The Comprehensive Cancer Center, University of Alabama at Birmingham, 35294, USA. safavy@uab.edu
authors.forename: A
authors.initials: A
authors.lastname: Safavy
authors.forename: K P
authors.initials: KP
authors.lastname: Raisch
authors.forename: M B
authors.initials: MB
authors.lastname: Khazaeli
authors.forename: D J
authors.initials: DJ
authors.lastname: Buchsbaum
authors.forename: J A
authors.initials: JA
authors.lastname: Bonner
mesh_terms: D000970:Antineoplastic Agents / Q000097:blood / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D009842:Oligopeptides / Q000737:chemistry / Q000378:metabolism; D017239:Paclitaxel / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011092:Polyethylene Glycols / Q000737:chemistry; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018004:Receptors, Bombesin / Q000378:metabolism; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; C401330:BBN peptide (7-13); D009842:Oligopeptides; D011355:Prodrugs; D018004:Receptors, Bombesin; D011092:Polyethylene Glycols; D017239:Paclitaxel