Nonconventional trans-Platinum Complexes Functionalized with RDG Peptides: Chemical and Cytototoxicity Studies

In order for platinum complexes to target cancer cells, trans-Pt-II or trans-Pt-IV complexes were bioconjugated to the cyclic peptide cRGDfK (cRGD), which has an affinity for a(v)beta(3)-integrin receptors, through its 4-picolinic acid spectator ligands. To tackle this goal, the Pt-II and Pt-IV precursors were activated at their carboxylic acid functional group, and futher treated with the cRGDfK peptide, to afford the bioconjugates Pt-II-cRGD and Pt-IV-cRGD, respectively. Pt-II-cRGD was studied by Pt-195 NMR spectroscopy, which confirmed the presence of the Pt-II center. In contrast, the characterization of Pt-IV-cRGD was not possible, due to the tendency of this complex to undergo reduction to Pt-II in solution. Thus, only the Pt-II-cRGD complex was used for further biological studies, and it exhibited some cytotoxic activity against the HUVEC (human umbilical vein endothelial cells) cell line, which has the highest levels of a(v)beta(3) expression. However, no improved effects were observed with respect to the Pt-II-pic precursor. Studies by ICP-MS showed enhanced intracellular accumulation for Pt-II-cRGD, with respect to Pt-II-pic in cancer cells. Overall, these results show that, while Pt-II bioconjugation enhances the uptake of the compound, it did not translate into increased cytotoxicity.