Novel one−/two-photon excited β-carboline/quinolinium photosensitizers for hypoxia-resistant tumor photodynamic therapy through apoptosis and necrosis

Photodynamic therapy (PDT) represents an innovative modality that employs photosensitizer for the treatment of tumors, dermatological conditions, and vascular disorders. Herein, a series of novel photosensitizers 2a-e were designed and synthesized by incorporating quinolinium into the β-carboline. In particular, photosensitizer 2d generated a large amount of type-I/-II active oxygen species, including ¹O₂, •O₂^-, and •OH under one-/two-photon excitation. Furthermore, 2d effectively overcame the tumor hypoxic microenvironment and exhibited strong one-/two-photon photodynamic activities against HT29 cells (IC₅₀s = 0.18-0.56 μM, PIs = 88-263). Additionally, 2d could significantly induce cancer cell apoptosis via reducing Bcl-2 and increasing Bax/Cleaved-caspase-3, and simultaneously promote programmed necrosis through boosting P-MLKL and P-RIPK1/3 expression. In vivo experiments substantiated that 2d powerfully suppressed colonic tumor growth under one-/two-photon irradiation (suppression rates 77-91 %). Therefore, this work may provide an effective approach for designing novel β-carboline/quinolinium photosensitizers and present a promising prospect in the field of one-/two-photon tumor photodynamic therapy.