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

• Published in: Bioconjugate chemistry 2012-09, Vol.23 (9), p.1838-1855
• Main Authors: Barragán, Flavia, Carrion-Salip, Dolors, Gómez-Pinto, Irene, González-Cantó, Alejandro, Sadler, Peter J, de Llorens, Rafael, Moreno, Virtudes, González, Carlos, Massaguer, Anna, Marchán, Vicente
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Cancer; Cancer cells; Cancer chemotherapy; Cell Line, Tumor; Cell receptors; Cells; Chromatography, High Pressure Liquid; Càncer; Cèl·lules canceroses; Gene expression; Humans; Immunohistochemistry; Magnetic Resonance Spectroscopy; Metals - chemistry; Peptides; Protein synthesis; Pèptids; Quimioteràpia del càncer; Receptors cel·lulars; Receptors, Somatostatin - drug effects; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Statins; Tumors
• ISSN: 1043-1802; 1520-4812
• DOI: 10.1021/bc300173h

Conjugates of a dicarba analogue of octreotide, a potent somatostatin agonist whose receptors are overexpressed on tumor cells, with [PtCl2(dap)] (dap = 1-(carboxylic acid)-1,2-diaminoethane) (3), [(η6-bip)Os(4-CO2-pico)Cl] (bip = biphenyl, pico = picolinate) (4), [(η6-p-cym)RuCl(dap)]+ (p-cym = p-cymene) (5), and [(η6-p-cym)RuCl(imidazole-CO2H)(PPh3)]+ (6), were synthesized by using a solid-phase approach. Conjugates 3–5 readily underwent hydrolysis and DNA binding, whereas conjugate 6 was inert to ligand substitution. NMR spectroscopy and molecular dynamics calculations showed that conjugate formation does not perturb the overall peptide structure. Only 6 exhibited antiproliferative activity in human tumor cells (IC50 = 63 ± 2 μM in MCF-7 cells and IC50 = 26 ± 3 μM in DU-145 cells) with active participation of somatostatin receptors in cellular uptake. Similar cytotoxic activity was found in a normal cell line (IC50 = 45 ± 2.6 μM in CHO cells), which can be attributed to a similar level of expression of somatostatin subtype-2 receptor. These studies provide new insights into the effect of receptor-binding peptide conjugation on the activity of metal-based anticancer drugs, and demonstrate the potential of such hybrid compounds to target tumor cells specifically.