Toward Angiogenesis Inhibitors Based on the Conjugation of Organometallic Platinum(II) Complexes to RGD Peptides

Abstract

A novel conjugate between a cyclometalated platinum(II) complex with dual antiangiogenic and antitumor activity and a cyclic peptide containing the RGD sequence (-Arg-Gly-Asp-) has been synthesized by combining solid- and solution-phase methodologies. Although peptide conjugation rendered a non-cytotoxic compound in all tested tumor cell lines (± α β and α β integrin receptors), the antiangiogenic activity of the Pt-c(RGDfK) conjugate in human umbilical vein endothelial cells at sub-cytotoxic concentrations opens the way to the design of a novel class of angiogenesis inhibitors through conjugation of metallodrugs with high antiangiogenic activity to cyclic RGD-containing peptides or peptidomimetic analogues.

RGD Peptide‐Drug Conjugates as Effective Dual Targeting Platforms: Recent Advances

“…The development of bioactive metallodrugs with dual cytotoxic and antiangiogenic properties holds promise as an alternative to classical cisplatin‐based drugs in chemotherapy. To this aim, Marchán, Ruiz and colleagues [42] proposed the synthesis and biological evaluation of a robust covalent conjugate (compound 7 , Scheme 4) embodying the cilengitide analogue c (RGDfK) and the cyclometalated Pt(II)‐DMBA complex, which had previously demonstrated to display antiangiogenic and antitumor activities at sub‐micromolar concentrations [43] . Unfortunately, cytotoxicity studies in vitro revealed that conjugation to the RGD peptide resulted in a dramatic decrease of antiproliferative activity with respect to the unconjugated Pt‐DMBA complex reference, while the antiangiogenic activity was retained at sub‐cytotoxic concentrations and was similar to that of reference cyclopeptide c (RGDfK) alone.…”

Building up PtII−Thiosemicarbazone−Lysine−sC18 Conjugates

“…However, although promising, metal complexes are generally only less developed as pharmaceutics owing to their poor water solubility and limited cellular uptake [30] . One way to overcome these issues is the combination of metal complexes with bioactive peptides, which has gained considerable attention during the last decade [31–41] . In this context, so‐called cell‐penetrating peptides (CPPs) are promising tools to deliver metal complexes into various types of cells [41–49] .…”

Monofunctional Platinum(II) Anticancer Agents

“…In the case of tumor-induced angiogenesis, transmembrane receptors such as integrins (α v β 3 and α v β 5 ) are highly expressed, which have a very high affinity for peptides containing RGD (Arg-Gly-Asp) and NGR (Asn-Gly-Arg) sequences. In this regard, complex 26 ( Figure 10) with dual antiangiogenic and antitumor activity was a non-cytotoxic compound with IC 50 >100 µM in different cancer cell lines (± α v β 3 and α v β 5 integrin receptors), while showing the antiangiogenic activity in HUVECs at sub-cytotoxic concentrations [89], which exemplified the design of angiogenesis inhibitors through conjugating a metallodrug with antiangiogenic activity to a cyclic RGD-containing peptide or a peptidomimetic analogue. Targeting angiogenesis provides an alternative direction for tumor-targeting therapy [90].…”