Hydroxyflavone-Modified Aza-BODIPY Derivatives for Combined Photodynamic and CO Therapy against Neuroblastoma

Hydroxyflavone-modified aza-BODIPY derivatives were developed as metal-free photosensitizers integrating photodynamic therapy (PDT) with singlet oxygen-triggered carbon monoxide (CO) release for neuroblastoma treatment. The compounds exhibit near-infrared absorption, efficient singlet oxygen generation, and light-controlled CO release via hydroxyflavone decarbonylation. Among the series, AF-I demonstrated superior phototherapeutic activity compared with the non-CO-releasing analogue and reference PDT/CO systems under identical conditions. Mechanistic studies indicate that PDT serves as the primary cytotoxic pathway, while localized CO release functions as a sensitizing component that enhances oxidative stress-induced apoptosis. AF-I retained improved phototoxicity under hypoxic conditions, suggesting partial preservation of PDT efficacy when oxygen availability is limited. Zebrafish biodistribution studies revealed limited blood-brain barrier penetration, supporting potential application in extracranial neuroblastoma. This work establishes a metal-free strategy for integrating controlled gasotransmitter release with PDT and provides a molecular framework for next-generation light-activated combination phototherapeutics.