Affiliation:
1. State Key Laboratory of Fine Chemicals, Frontiers Science Center for Smart Materials Dalian University of Technology Dalian 116024 China
2. State Key Laboratory of Molecular Reaction Dynamics and Collaborative Innovation Center of Chemistry for Energy Materials Dalian Institute of Chemical Physics Chinese Academy of Sciences Dalian 116023 China
3. Key Lab of Colloid and Interface Chemistry Shandong University Jinan 250100 China
4. Ningbo Institute of Dalian University of Technology Dalian University of Technology Ningbo 315016 China
Abstract
AbstractThe clinical application of photodynamic therapy (PDT) is limited by oxygen‐dependence and side effects caused by photosensitizer residues. Photoinitiators based on the H‐abstraction reaction can address these challenges because they can generate alkyl radical‐killing cells independently of oxygen and undergo rapid bleaching following H‐abstraction. Nonetheless, the development of photoinitiators for PDT has been impeded by the absence of effective design strategies. Herein, we have developed aryl‐ketone substituted cyanine (ACy−R), the first red‐light triggered H‐abstraction photoinitiators for hypoxic cancer therapy. These ACy−R molecules inherited the near‐infrared absorption of cyanine dye, and aryl‐ketone modification imparted H‐abstraction capability. Experimental and quantum calculations revealed that modifying the electron‐withdrawing groups of the aryl (e.g., ACy‐5F) improved the contribution of the O atom to the photon excitation process promoting intersystem crossing and H‐abstraction ability. Particularly, ACy‐5F rapidly penetrated cells and enriched in the endoplasmic reticulum. Even under severe hypoxia, ACy‐5F initiated red‐light induced H‐abstraction with intracellular biomolecules, inducing necroptosis and ferroptosis. Moreover, ACy‐5F was degraded after H‐abstraction, thus avoiding the side effects of long‐term phototoxicity after therapy. This study not only provides a crucial molecular tool for hypoxic tumors therapy, but also presents a promising strategy for the development of multifunctional photosensitizers and photoinitiators.