Conjugated Platinum(IV)−Peptide Complexes for Targeting Angiogenic Tumor Vasculature

Abstract

The integrins α v β 3 and α v β 5 and the membrane-spanning surface protein aminopeptidase-N (APN) are highly expressed in tumor-induced angiogenesis, making them attractive targets for therapeutic intervention. Both integrins and APN recognize a broad range of peptides containing RGD (ArgGly-Asp) and NGR (Asn-Gly-Arg) motifs, respectively. Here, we describe the design, synthesis, and characterization of a series of mono-and difunctionalized platinum(IV) complexes in which a conjugated peptide motif, containing either RGD, CRGDC, (RGDfK)c or NGR, is appended as a 'tumor-homing device' to target tumor endothelial cells selectively over healthy cells. Platinum(IV)-peptide complexes with non-specific amino acids or peptide moieties were prepared as controls. Concentration-response curves of these compounds were evaluated against primary proliferating endothelial cells and tumor cell lines and compared to those of cisplatin, a well-described platinumbased chemotherapeutic agent. The Pt(IV)-RGD conjugates were highly and specifically cytotoxic to α v β 3 and α v β 5 containing cell lines, approaching the activity of cisplatin. The Pt(IV)-NGR complexes were less active than Pt(IV)-RGD-containing compounds but more active than nonspecific Pt-peptide controls. Integrin α v β 3 mediated, at least in part, the anti-proliferative effect of an Pt(IV)-RGD conjugate, as demonstrated by a decreased inhibitory response when endothelial cells were either (1) incubated with an excess of α v β 3 /α v β 3 -specific RGD pentapeptides, or (2) transfected with RNAi for β 3 , but not β 1 , integrins. These results suggest a rational approach to improved chemotherapy with Pt(IV)-peptide conjugates by selective drug delivery to the tumor compartment.

Somatostatin Subtype-2 Receptor-Targeted Metal-Based Anticancer Complexes

“…25 In recent years, several coordination or organometallic complexes have also been conjugated to carrier molecules such as receptor-binding peptides or known delivery peptides to improve both cellular uptake to cancer cells and cytotoxic activity of the metal-based drug. 26,27,28,29,30,31,32,33 Herein we report on the use of conjugates between octreotide and several metal complexes as new chemotherapeutic agents. In particular, the synthesis of hybrid compounds between the dicarba analogue of octreotide (2) and platinum(II), ruthenium(II) and osmium(II) metal complexes has been accomplished by efficient solid-phase procedures (compounds 3-6 in Chart 1).…”

In vitro assessment of the cytotoxic effects of novel RGD analogues

“…RGD peptides conjugated with different cytostatic agents are likely to exhibit an antitumour and antiangiogenic synergetic effect. During the last few years, a number of RGD-cytotoxic drugs were developed and showed promising activities in vitro and in vivo [15,16].…”

Mitaplatin, a potent fusion of cisplatin and the orphan drug dichloroacetate

“…To overcome tumor cell resistance and toxicity to normal tissues, we have been exploring strategies to target platinum constructs to cancer cells. Our tactic has been to employ substitutionally inert platinum(IV) compounds (24), which serve as prodrugs and release clinically effective levels of platinum(II) compounds, such as cisplatin, following cellular uptake (25)(26)(27). Appropriately designed platinum(IV) complexes are less likely to be deactivated before reaching their cancer cell destination target.…”