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.
Titolo: | Synthesis and biological evaluation (in Vitro and in Vivo) of cyclic arginine-glycine-aspartate (RGD) peptidomimetic-paclitaxel conjugates targeting integrin αvβ3 |
Autori: | COLOMBO, RAFFAELE (Primo) MINGOZZI, MICHELE (Secondo) SCANZIANI, EUGENIO (Penultimo) GENNARI, CESARE MARIO ARTURO (Ultimo) |
Parole Chiave: | integrin antagonists; drug-delivery; enantioselective synthesis; mitotic catastrophe; tumor angiogenesis; divalent peptide; mouse model; design; cancer; inhibitors |
Settore Scientifico Disciplinare: | Settore CHIM/06 - Chimica Organica Settore CHIM/08 - Chimica Farmaceutica Settore BIO/14 - Farmacologia |
Data di pubblicazione: | 2012 |
Rivista: | |
Tipologia: | Article (author) |
Digital Object Identifier (DOI): | http://dx.doi.org/10.1021/jm301058f |
Appare nelle tipologie: | 01 - Articolo su periodico |
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