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.

New pyridin-3-ylmethyl carbamodithioic esters activate pyruvate kinase M2 and potential anticancer lead compounds

“…As no reported PKM2 activators exhibit cellular activity, the antitumor drug Taxol was selected as positive control to test the sensitivity of the model. As shown in Table 2, the result of Taxol was consistent with previous reports, 30,31 confirming the accuracy of our experiment. The IC 50 values of tested compounds against different tumor cells ranged between 0.64 and 5.6 µM.…”

Effective Inhibition of Experimental Human Ovarian Cancers with a Targeted Cytotoxic Bombesin Analogue AN-215

“…AN-215 has been shown more effective than its nontargeted cytotoxic radical, AN-201 in preclinical models of various malignancies, such as SCLC, gastric carcinoma, prostate cancer, and glioblastoma (41 -44). Recently, the synthesis of paclitaxel derivatives of bombesin analogues has been reported (45).…”

Targeting gastrin releasing peptide receptors: New options for the therapy and diagnosis of cancer

“…59 The cytotoxicity against H1299 human non small cell lung cancer was enhanced compared with unconjugated taxol. Recently, a multiligand compound, consisting of two BN [6][7][8][9][10][11][12][13][14] and one paclitaxel with enhanced cytotoxic activity against several GRP-R positive human cancer cell lines was synthesized.…”