Paclitaxel derivatives for targeted therapy of cancer: Toward the development of smart taxanes

被引:99
作者
Safavy, A
Raisch, KP
Khazaeli, MB
Buchsbaum, DJ
Bonner, JA
机构
[1] Univ Alabama Birmingham, Dept Radiat Oncol, Birmingham, AL 35294 USA
[2] Univ Alabama Birmingham, Dept Med, Birmingham, AL 35294 USA
[3] Univ Alabama Birmingham, Ctr Comprehens Canc, Birmingham, AL 35294 USA
关键词
D O I
10.1021/jm990355x
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
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 IC50 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.
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页码:4919 / 4924
页数:6
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