title: Synthesis and biological evaluation (in vitro and in vivo) of cyclic arginine-glycine-aspartate (RGD) peptidomimetic-paclitaxel conjugates targeting integrin αVβ3.
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.
authors.affiliation: Dipartimento di Chimica, Università degli Studi di Milano, Via Golgi 19, I-20133, Milan, Italy.
authors.forename: Raffaele
authors.initials: R
authors.lastname: Colombo
authors.forename: Michele
authors.initials: M
authors.lastname: Mingozzi
authors.forename: Laura
authors.initials: L
authors.lastname: Belvisi
authors.forename: Daniela
authors.initials: D
authors.lastname: Arosio
authors.forename: Umberto
authors.initials: U
authors.lastname: Piarulli
authors.forename: Nives
authors.initials: N
authors.lastname: Carenini
authors.forename: Paola
authors.initials: P
authors.lastname: Perego
authors.forename: Nadia
authors.initials: N
authors.lastname: Zaffaroni
authors.forename: Michelandrea
authors.initials: M
authors.lastname: De Cesare
authors.forename: Vittoria
authors.initials: V
authors.lastname: Castiglioni
authors.forename: Eugenio
authors.initials: E
authors.lastname: Scanziani
authors.forename: Cesare
authors.initials: C
authors.lastname: Gennari
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry* / Q000494:pharmacology; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D039302:Integrin alphaVbeta3 / Q000187:drug effects*; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D009842:Oligopeptides / Q000737:chemistry* / Q000494:pharmacology; D017239:Paclitaxel / Q000737:chemistry* / Q000494:pharmacology; D057786:Peptidomimetics; D021241:Spectrometry, Mass, Electrospray Ionization
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D039302:Integrin alphaVbeta3; D009842:Oligopeptides; D057786:Peptidomimetics; C047981:arginyl-glycyl-aspartic acid; D017239:Paclitaxel