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

In order for platinum complexes to target cancer cells, trans‐PtII or trans‐PtIV complexes were bioconjugated to the cyclic peptide cRGDfK (cRGD), which has an affinity for αvβ3‐integrin receptors, through its 4‐picolinic acid spectator ligands. To tackle this goal, the PtII and PtIV precursors were activated at their carboxylic acid functional group, and futher treated with the cRGDfK peptide, to afford the bioconjugates PtII–cRGD and PtIV–cRGD, respectively. PtII–cRGD was studied by 195Pt NMR spectroscopy, which confirmed the presence of the PtII center. In contrast, the characterization of PtIV–cRGD was not possible, due to the tendency of this complex to undergo reduction to PtII in solution. Thus, only the PtII–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 αvβ3 expression. However, no improved effects were observed with respect to the PtII–pic precursor. Studies by ICP‐MS showed enhanced intracellular accumulation for PtII–cRGD, with respect to PtII–pic in cancer cells. Overall, these results show that, while PtII bioconjugation enhances the uptake of the compound, it did not translate into increased cytotoxicity. We present the conjugation of the cyclic peptide cRGDfK (cRGD) to trans‐PtII or trans‐PtIV complexes through its 4‐picolinic acid spectator ligand.