Design, Synthesis, and Biological Evaluation of Novel cRGD鈥揚aclitaxel Conjugates for Integrin-Assisted Drug Delivery

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• 作者：Michael Pilkington-Miksa ; Daniela Arosio ; Lucia Battistini ; Laura Belvisi ; Marilenia De Matteo ; Francesca Vasile ; Paola Burreddu ; Paola Carta ; Gloria Rassu ; Paola Perego ; Nives Carenini ; Franco Zunino ; Michelandrea De Cesare ; Vittoria Castiglioni ; Eugenio Scanziani ; Carlo Scolastico ; Giovanni Casiraghi ; Franca Zanardi ; Leonardo Manzoni
• 刊名：Bioconjugate Chemistry
• 出版年：2012
• 出版时间：August 15, 2012
• 年：2012
• 卷：23
• 期：8
• 页码：1610-1622
• 全文大小：615K
• 年卷期：v.23,no.8(August 15, 2012)
• ISSN：1520-4812

文摘

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 伪_V尾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.