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Dal Pozzo A.,Istituto di Ricerche Chimiche e Biochimiche nzoni | Ni M.-H.,Istituto di Ricerche Chimiche e Biochimiche nzoni | Esposito E.,Istituto di Ricerche Chimiche e Biochimiche nzoni | Dallavalle S.,University of Milan | And 10 more authors.
Bioorganic and Medicinal Chemistry

Five RGD peptide-camptothecin (CPT) conjugates were designed and synthesized with the purpose to improve the therapeutic index of this antitumoral drug family. New RGD cyclopeptides were selected on the basis of their high affinity to αv integrin receptors overexpressed by tumor cells and their metabolic stability. The conjugates can be divided in two groups: in the first the peptide was attached to the drug through an amide bond, in the second through a hydrazone bond. The main difference between the two spacers lies in their acid stability. Affinity to the receptors was maintained for all conjugates and their internalization into tumor cells was demonstrated. The first group conjugates showed lower in vitro and in vivo activity than the parent drug, probably due to the excessive stability of the amide bond, even inside the tumor cells. Conversely, the hydrazone conjugates exhibited in vitro tumor cell inhibition similar to the parent drug, indicating high conversion in the culture medium and/or inside the cells, but their poor solubility hampered in vivo experiments. On the basis of these results, information was acquired for additional development of derivatives with different linkers and better solubility for in vivo evaluation. © 2009 Elsevier Ltd. All rights reserved. Source

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