Design, synthesis, and biological evaluation of novel cRGD-paclitaxel conjugates for integrin-assisted drug delivery

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

Research output: Contribution to journalArticlepeer-review


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 αVβ3 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.

Original languageEnglish
Pages (from-to)1610-1622
Number of pages13
JournalBioconjugate Chemistry
Issue number8
Publication statusPublished - Aug 15 2012

ASJC Scopus subject areas

  • Biotechnology
  • Bioengineering
  • Organic Chemistry
  • Pharmaceutical Science
  • Biomedical Engineering
  • Pharmacology


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