Synthesis and biological evaluation of RGD peptidomimetic-paclitaxel conjugates bearing lysosomally cleavable linkers

Being overexpressed on blood vessels in human tumors, but not on vessels in normal human tissues, the transmembrane glycoprotein αVβ3 integrin has become an attractive target in the oncology area. The Gennari and Piarulli group recently developed a peptidomimetic compound (1) containing the RGD (Arg-Gly-Asp) sequence and a diketopiperazine (DKP) scaffold as powerful αVβ3 integrin ligand. 1) A functionalized analogue of this ligand (2)2 was linked to Paclitaxel through two different lysosomally cleavable linkers (the Val-Ala peptide sequence in compound 3 and the Phe-Lys in compound 4). The antiproliferative activities of the conjugates were evaluated against two isogenic cell lines expressing αvβ3 at different levels: the acute lymphoblastic leukemia cell line CCRF-CEM (αvβ3 −) and its subclone CCRF-CEM αvβ3 (αvβ3 +). A fairly effective integrin-targeting was displayed by conjugate 3, which was found to inhibit cell proliferation with increased selectivity towards αvβ3-expressing cells compared to the free PTX. We gratefully acknowledge MIUR for financial support (PRIN project 2010NRREPL: Synthesis and Biomedical Applications of Tumor-Targeting Peptidomimetics).