Bombesin-Targeted Delivery of β‑Carboline-Based Ir(III) and Ru(II) Photosensitizers for a Selective Photodynamic Therapy of Prostate Cancer

• Published in: Inorganic chemistry Vol. 63; no. 41; pp. 19140 - 19155
• Main Authors: Sanz-Villafruela, Juan, Bermejo-Casadesús, Cristina, Riesco-Llach, Gerard, Iglesias, Mònica, Martínez-Alonso, Marta, Planas, Marta, Feliu, Lidia, Espino, Gustavo, Massaguer, Anna
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 14.10.2024
• ISSN: 0020-1669; 1520-510X; 1520-510X
• DOI: 10.1021/acs.inorgchem.4c02583

Despite advances in Ir­(III) and Ru­(II) photosensitizers (PSs), their lack of selectivity for cancer cells has hindered their use in photodynamic therapy (PDT). We disclose the synthesis and characterization of two pairs of Ir­(III) and Ru­(II) polypyridyl complexes bearing two β-carboline ligands (N^N’) functionalized with −COOMe (L1) or −COOH (L2), resulting in PSs of formulas [Ir­(C^N)2(N^N’)]Cl (Ir-Me: C^N = ppy, N^N’ = L1; Ir-H: C^N = ppy, N^N’ = L2) and [Ru­(N^N)2(N^N’)]­(Cl)2 (Ru-Me: N^N = bpy, N^N’ = L1; Ru-H: N^N = bpy, N^N’ = L2). To enhance their selectivity toward cancer cells, Ir-H and Ru-H were coupled to a bombesin derivative (BN3), resulting in the metallopeptides Ir-BN and Ru-BN. Ir­(III) complexes showed higher anticancer activity than their Ru­(II) counterparts, particularly upon blue light irradiation, but lacked cancer cell selectivity. In contrast, Ir-BN and Ru-BN exhibited selective photocytoxicity against prostate cancer cells, with a lower effect against nonmalignant fibroblasts. All compounds generated ROS and induced severe mitochondrial toxicity upon photoactivation, leading to apoptosis. Additionally, the ability of Ir-Me to oxidize NADH was demonstrated, suggesting a mechanism for mitochondrial damage. Our findings indicated that the conjugation of metal PSs with BN3 creates efficient PDT agents, achieving selectivity through targeting bombesin receptors and local photoactivation.