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

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

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)10460-10474
Number of pages15
JournalJournal of Medicinal Chemistry
Volume55
Issue number23
DOIs
Publication statusPublished - Dec 13 2012

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Fingerprint Dive into the research topics of 'Synthesis and biological evaluation (in Vitro and in Vivo) of cyclic arginine-glycine-aspartate (RGD) peptidomimetic-paclitaxel conjugates targeting integrin α<sub>v</sub>β<sub>3</sub>'. Together they form a unique fingerprint.

Cite this