Unimolecular Photodynamic O2-Economizer to Overcome Hypoxia Resistance in Phototherapeutics

Tumor hypoxia has proven to be the major bottleneck of photodynamic therapy (PDT) to clinical transformation. Different from traditional O2 delivery approaches, here we describe an innovative binary photodynamic O2-economizer (PDOE) tactic to reverse the hypoxia-driven resistance by designing superoxide radical (O2−•) generator targeting mitochondria respiration, termed SORgenTAM. Such PDOE system is able to block the intracellular O2 consumption and down-regulate HIF-1 ex-pression, which successfully rescue cancer cells from becoming hypoxia and relieve the intrinsic hypoxia burden of tumors in vivo, thereby sparing sufficient endogenous O2 for PDT process. Photosensitization mechanism studies demonstrate that SORgenTAM has ideal intersystem crossing rate and triplet excited state lifetime for generating O2−• through type-I photochemistry, and the generated O2−• can further trigger bio-cascade to reduce the PDT’s demand for O2 in an O2-recycble manner. Furthermore, SORgenTAM also serves to activate AMPK...