Mechanistic Insights into Oxygen‐Independent DNA Photodegradation by Pheophorbide <i>a</i>: Implications for Future Photodynamic Therapy Applications

This study explores the unique properties of Pheophorbide a (Phed a) in the photodegradation of G-quadruplex DNA under anoxic conditions, emphasizing its potential for photodynamic therapy (PDT) in hypoxic tumor environments. We used electron spin resonance (ESR), circular dichroism (CD), and nuclear magnetic resonance (NMR) spectroscopies to assess the radical generation and DNA interaction capabilities of Phed a compared to Pyropheophorbide a (Pyro a) under both oxygenated and anoxic conditions. Our results reveal that Phed a effectively degrades G-quadruplex DNA in the absence of oxygen, whereas Pyro a does not. Under anoxic conditions, Phed a generates unique carbon-centered radicals, as indicated by distinctive ESR signals, which are not observed in aerobic environments or with Pyro a. These radicals facilitate DNA decomposition without relying on reactive oxygen species (ROS). Phed a's ability to degrade DNA independently of oxygen underscores its potential as a versatile and effective PDT agent, especially for hypoxic tumors where traditional photosensitizers are ineffective. This study paves the way for the development of new PDT agents that can operate under different oxygen levels. Phed a's radical generation and oxygen-independent DNA degradation mechanisms make it a promising candidate for future PDT applications.