Synthesis and biological evaluation (in vitro and in vivo) of cyclic arginine-glycine-aspartate (RGD) peptidomimetic-paclitaxel conjugates targeting integrin αVβ3.
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| 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 αVβ3 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 αVβ3, 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.
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| Authors | 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 |
| Journal | Journal of medicinal chemistry (J Med Chem) Vol. 55 Issue 23 Pg. 10460-74 (Dec 13 2012) ISSN: 1520-4804 [Electronic] United States |
| PMID | 23140358 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't) |
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