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

The pharmacologic efficacy of the promising antitumor agent paclitaxel (Tax ol) may be potentially enhanced through derivatization of the drug to a wat er-soluble tumor-recognizing conjugate. This work reports the design and sy nthesis of the first tumor-directed derivative of paclitaxel. A 7-amino aci d synthetic peptide, BBN[7-13], which binds to the cell surface bombesin/ga strin-releasing peptide (BBN/GRP) receptor, was conjugated to the paclitaxe l-2'-hydroxy function by a heterobifunctional poly(ethylene glycol) linker. The resulting conjugate, designated PTXPEGBBN[7-13], was soluble to the up per limit of tested concentrations (250 mg/mL). The conjugate completely re tained the receptor binding properties of the attached peptide as compared with those of the unconjugated BBN[7-13]. In experiments with NCI-H1299 hum an 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 fact or 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 paclitaxe l prodrug which may establish a new mode for the utilization of this drug i n cancer therapy.