A small library of integrin ligand paclitaxel conjugates 10-13 was synthesized with the aim of using the tumor-homing cyclo[DKP-RGD] peptidomimetics for site-directed delivery of the cytotoxic drug. All the paclitaxel-RGD constructs 10-13 inhibited biotinylated vitronectin binding to the purified alpha(v)beta(3) integrin receptor at low nanomolar concentration and showed in vitro cytotoxic activity against a panel of human tumor cell lines similar to that of paclitaxel. Among the cell lines, the cisplatin-resistant IGROV-1/Pt1 cells expressed high levels of integrin alpha(v)beta(3), making them attractive to be tested in in vivo models. cyclo[DKP-f3-RGD]-PTX 11 displayed sufficient stability in physiological solution and in both human and murine plasma to be a good candidate for in vivo testing. In tumor-targeting experiments against the IGROV-1/Pt1 human ovarian carcinoma xenotransplanted in nude mice, compound 11 exhibited a superior activity compared with paclitaxel, despite the lower (about half) molar dosage used.

Synthesis and biological evaluation (in Vitro and in Vivo) of cyclic arginine-glycine-aspartate (RGD) peptidomimetic-paclitaxel conjugates targeting integrin αvβ3 / R. Colombo, M. Mingozzi, L. Belvisi, D. Arosio, U. Piarulli, N. Carenini, P. Perego, N. Zaffaroni, M. De Cesare, V. Castiglioni, E. Scanziani, C. Gennari. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - 55:23(2012), pp. 10460-10474.

Synthesis and biological evaluation (in Vitro and in Vivo) of cyclic arginine-glycine-aspartate (RGD) peptidomimetic-paclitaxel conjugates targeting integrin αvβ3

R. Colombo;M. Mingozzi;L. Belvisi;V. Castiglioni;E. Scanziani;C. Gennari
2012

Abstract

A small library of integrin ligand paclitaxel conjugates 10-13 was synthesized with the aim of using the tumor-homing cyclo[DKP-RGD] peptidomimetics for site-directed delivery of the cytotoxic drug. All the paclitaxel-RGD constructs 10-13 inhibited biotinylated vitronectin binding to the purified alpha(v)beta(3) integrin receptor at low nanomolar concentration and showed in vitro cytotoxic activity against a panel of human tumor cell lines similar to that of paclitaxel. Among the cell lines, the cisplatin-resistant IGROV-1/Pt1 cells expressed high levels of integrin alpha(v)beta(3), making them attractive to be tested in in vivo models. cyclo[DKP-f3-RGD]-PTX 11 displayed sufficient stability in physiological solution and in both human and murine plasma to be a good candidate for in vivo testing. In tumor-targeting experiments against the IGROV-1/Pt1 human ovarian carcinoma xenotransplanted in nude mice, compound 11 exhibited a superior activity compared with paclitaxel, despite the lower (about half) molar dosage used.
integrin antagonists; drug-delivery; enantioselective synthesis; mitotic catastrophe; tumor angiogenesis; divalent peptide; mouse model; design; cancer; inhibitors
Settore CHIM/06 - Chimica Organica
Settore CHIM/08 - Chimica Farmaceutica
Settore BIO/14 - Farmacologia
JOURNAL OF MEDICINAL CHEMISTRY
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/214316
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