Photoinduced electron transfer enhances the tumor-targeted photodynamic activity of bombesin metallopeptides incorporating an Ir(III) complex and carboxyfluorescein

Abstract

A primary objective of photodynamic therapy (PDT) is to develop tumor-targeted photosensitizers (PS) that enable selective cytotoxicity through preferential accumulation in cancer tissues and local activation by light. Here, we report on the synthesis of two novel Ir(III) PSs (1 and 2), designed with a terminal alkynyl moiety for subsequent peptide conjugation via click chemistry. Both complexes demonstrated photocatalytic activity, efficiently generating singlet oxygen (1O2). Complex 1 also exhibited remarkable phototoxicity, achieving nanomolar IC50 values in several cancer cell lines following light exposure. Complex 1 accumulated mainly in mitochondria, where it triggered membrane depolarization and apoptosis upon photoactivation, without affecting the cell cycle. To enhance tumor selectivity, 1 was conjugated to different derivatives of the tumor-targeting peptide bombesin, yielding 13 metallopeptides. Although conjugation reduced the cytotoxicity of 1, some metallopeptides were 2–4 times more active against PC3 cancer cells than healthy fibroblasts, which confirmed their improved selectivity. A double-functionalized metallopeptide bearing both 1 and carboxyfluorescein (CF) at the N-terminal Lys (1-Tr-Lys(CF)-NLS-BN3) was synthesized. This molecular architecture exhibited emission quenching relative to the metal-free derivative (CF-NLS-BN3) and an enhanced photodynamic effect compared to the CF-free metallopeptide (1-Tr-Lys-NLS-BN3). Based on photophysical studies, both observations were rationalized as a result of a photoinduced electron transfer process. The synergistic effect between the Ir and the CF fragments, combined with the peptide-mediated selectivity, offers significant insights for optimizing metal-based PSs for cancer therapy