Synthesis and Biological Evaluation (in Vitro and in Vivo) of Cyclic Arginine鈥揋lycine鈥揂spartate (RGD) Peptidomimetic鈥揚aclitaxel Conjugates Targeting Integrin 伪V尾3

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• 作者：Raffaele Colombo ; Michele Mingozzi ; Laura Belvisi ; Daniela Arosio ; Umberto Piarulli ; Nives Carenini ; Paola Perego ; Nadia Zaffaroni ; Michelandrea De Cesare ; Vittoria Castiglioni ; Eugenio Scanziani ; Cesare Gennari
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：December 13, 2012
• 年：2012
• 卷：55
• 期：23
• 页码：10460-10474
• 全文大小：757K
• 年卷期：v.55,no.23(December 13, 2012)
• ISSN：1520-4804

文摘

A small library of integrin ligand鈥損aclitaxel conjugates 10鈥?b>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鈥揜GD constructs 10鈥?b>13 inhibited biotinylated vitronectin binding to the purified 伪_V尾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 伪_V尾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.