title: Design, synthesis, and biological evaluation of novel cRGD-paclitaxel conjugates for integrin-assisted drug delivery.
abstract: The efficacy of taxane-based antitumor therapy is limited by several drawbacks which result in a poor therapeutic index. Thus, the development of approaches that favor selective delivery of taxane drugs (e.g., paclitaxel, PTX) to the disease area represents a truly challenging goal. On the basis of the strategic role of integrins in tumor cell survival and tumor progression, as well as on integrin expression in tumors, novel molecular conjugates were prepared where PTX is covalently attached to either cyclic AbaRGD (Azabicycloalkane-RGD) or AmproRGD (Aminoproline-RGD) integrin-recognizing matrices via structurally diverse connections. Receptor-binding assays indicated satisfactory-to-excellent α(V)β(3) binding capabilities for most conjugates, while in vitro growth inhibition assays on a panel of human tumor cell lines revealed outstanding cell sensitivity values. Among the nine conjugate ensemble, derivative 21, bearing a robust triazole ring connected to ethylene glycol units by an amide function and showing excellent cell sensitivity properties, was selected for in vivo studies in an ovarian carcinoma model xenografted in immunodeficient mice. Remarkable antitumor activity was attained, superior to that of PTX itself, which was associated with a marked induction of aberrant mitoses, consistent with the mechanism of action of spindle poisons. Overall, the novel cRGD-PTX conjugates disclosed here represent promising candidates for further advancement in the domain of targeted antitumor therapy.
authors: Centro Interdipartimentale Studi Biomolecolari e Applicazioni Industriali, Università degli Studi di Milano, Via Fantoli 16/15, I-20138 Milano, Italy.
authors: Michael
authors: M
authors: Pilkington-Miksa
authors: Daniela
authors: D
authors: Arosio
authors: Lucia
authors: L
authors: Battistini
authors: Laura
authors: L
authors: Belvisi
authors: Marilenia
authors: M
authors: De Matteo
authors: Francesca
authors: F
authors: Vasile
authors: Paola
authors: P
authors: Burreddu
authors: Paola
authors: P
authors: Carta
authors: Gloria
authors: G
authors: Rassu
authors: Paola
authors: P
authors: Perego
authors: Nives
authors: N
authors: Carenini
authors: Franco
authors: F
authors: Zunino
authors: Michelandrea
authors: M
authors: De Cesare
authors: Vittoria
authors: V
authors: Castiglioni
authors: Eugenio
authors: E
authors: Scanziani
authors: Carlo
authors: C
authors: Scolastico
authors: Giovanni
authors: G
authors: Casiraghi
authors: Franca
authors: F
authors: Zanardi
authors: Leonardo
authors: L
authors: Manzoni
mesh_terms: D000577:Amides / Q000737:chemistry; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D053961:Azabicyclo Compounds / Q000737:chemistry; D002138:Calibration; D045744:Cell Line, Tumor; D060326:Chemistry Techniques, Synthetic; D004337:Drug Carriers / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D015195:Drug Design; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D039302:Integrin alphaVbeta3 / Q000378:metabolism*; D051379:Mice; D017239:Paclitaxel / Q000737:chemistry* / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D011392:Proline / Q000031:analogs & derivatives / Q000737:chemistry; D019030:Receptors, Vitronectin / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000577:Amides; D000970:Antineoplastic Agents; D053961:Azabicyclo Compounds; D004337:Drug Carriers; D039302:Integrin alphaVbeta3; D010456:Peptides, Cyclic; D019030:Receptors, Vitronectin; C467925:aminoproline; C507169:cyclic arginine-glycine-aspartic acid peptide; C064660:integrin alphaVbeta5; D011392:Proline; D017239:Paclitaxel