TY - JOUR
T1 - Synthesis and biological evaluation (in Vitro and in Vivo) of cyclic arginine-glycine-aspartate (RGD) peptidomimetic-paclitaxel conjugates targeting integrin αvβ3
AU - Colombo, Raffaele
AU - Mingozzi, Michele
AU - Belvisi, Laura
AU - Arosio, Daniela
AU - Piarulli, Umberto
AU - Carenini, Nives
AU - Perego, Paola
AU - Zaffaroni, Nadia
AU - De Cesare, Michelandrea
AU - Castiglioni, Vittoria
AU - Scanziani, Eugenio
AU - Gennari, Cesare
PY - 2012/12/13
Y1 - 2012/12/13
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84870974922&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84870974922&partnerID=8YFLogxK
U2 - 10.1021/jm301058f
DO - 10.1021/jm301058f
M3 - Article
C2 - 23140358
AN - SCOPUS:84870974922
VL - 55
SP - 10460
EP - 10474
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 23
ER -