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

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 (<b>L1</b>) or -COOH (<b>L2</b>), resulting in PSs of formulas [Ir(C^N)₂(N^N')]Cl (<b>Ir-Me:</b> C^N = ppy, N^N' = <b>L1</b>; <b>Ir-H:</b> C^N = ppy, N^N' = <b>L2</b>) and [Ru(N^N)₂(N^N')](Cl)₂ (<b>Ru-Me:</b> N^N = bpy, N^N' = <b>L1; Ru-H:</b> N^N = bpy, N^N' = <b>L2</b>). To enhance their selectivity toward cancer cells, <b>Ir-H</b> and <b>Ru-H</b> were coupled to a bombesin derivative (<b>BN3</b>), resulting in the metallopeptides <b>Ir-BN</b> and <b>Ru-BN</b>. Ir(III) complexes showed higher anticancer activity than their Ru(II) counterparts, particularly upon blue light irradiation, but lacked cancer cell selectivity. In contrast, <b>Ir-BN</b> and <b>Ru-BN</b> 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 <b>Ir-Me</b> to oxidize NADH was demonstrated, suggesting a mechanism for mitochondrial damage. Our findings indicated that the conjugation of metal PSs with <b>BN3</b> creates efficient PDT agents, achieving selectivity through targeting bombesin receptors and local photoactivation.