Supramolecular Photodynamic Agents for Simultaneous Oxidation of NADH and Generation of Superoxide Radical

Abstract Given that Type-I photosensitizers (PSs) have excellent hypoxia tolerance, developing general approaches to prepare Type-I PSs has the potential to advance the progress of photodynamic therapy (PDT), but remains a challenge. In this work, we report a supramolecular strategy for the preparation of Type-I photodynamic agents which simultaneously generate strong oxidizing cationic radicals of PS and superoxide radicals by introducing electron acceptors to the existing Type-II PSs. As a proof-of-concept, three electron acceptors were designed and co-assembled with a classical PS (iodide BODIPY) to produce quadruple hydrogen-bonded supramolecular photodynamic agents. The photo-induced electron transfer from the PS to the adjacent electron acceptor occurs efficiently, leading to the generation of a strong oxidizing PS+• and an anionic radical of the acceptor, which further transfers an electron to oxygen to form O2−•. Impressively, in addition to generating O2−• efficiently, these photodynamic agents induce direct photocatalytic oxidation of 1,4-dihydronicotinamide adenine dinucleotide (NADH) with a turnover frequency as high as 53.7 min-1 (1~3 orders of magnitude higher than those of conventional transition-metal catalysts), which offers an oxygen-independent mechanism to damage tumors. These photodynamic agents exhibit superior PDT performance even under hypoxic conditions. Distinct solid tumor ablation in vivo was also achieved in tumor treatment of mouse models. This work provides a new strategy and fresh insight on the design and development of Type-I photodynamic agents.