Novel ꞵ-carboline/cyanoisoflavone photosensitizers for ferroptosis-induced efficient chemo-photodynamic synergistic cancer therapy

Abstract

Photodynamic therapy (PDT) is an emerging therapeutic modality to selectively eradicate pathological cells, such as cancer cells. Hence, we designed and synthesized a series of novel ꞵ-carboline/cyanoisoflavone photosensitizers A1-A3. All compounds possessed potent type-I/-II photodynamic properties. Especially, the optimized compound A2 produced large amounts of •O₂⁻, •OH, and ¹O₂ under irradiation, and exhibited a higher quantum yield of singlet oxygen (Φ_Δ = 0.92) than others. Furthermore, A2 not only exhibited potent cytotoxicity in HT29 cells, but also demonstrated prominent chemo-photodynamic effects with IC₅₀ values of 3.9–4.1 μM under normoxic and hypoxic conditions in HT29 cells, while exhibited minimal toxicity to normal cells, suggesting its tumor-selective and hypoxia-tolerant efficacy. Most importantly, A2 significantly promoted mitochondrial damage and ferroptosis, through depleting GSH/GPX-4 levels and increasing malondialdehyde (MDA) expression. Finally, in vivo studies showed that A2 achieved a high colonic tumor-inhibitory rate of 84.6 % through chemo-photodynamic therapy. These findings provide a promising framework for the development of novel photosensitizers for chemo-photodynamic therapy.