NRNC-8, a novel mitochondria-immobilization superoxide radical generator for photodynamic therapy

Abstract

Mitochondria play an important role in carcinogenesis, and alterations in mitochondrial activity are frequently associated with cancer formation. Mitochondria have become attractive targets for cancer therapy, with mitochondria-targeted photodynamic therapy (PDT) being one of the most prominent fields. However, significant limitations remain, such as low spectroscopic absorption, short photosensitizer absorption wavelengths, and organelle targeting stability deterioration during phototherapy. In this work, we synthesized an Aza-Nile red-structured near-infrared photosensitizer NRNC-8 based on side-chain engineering for the first time. NRNC-8 can be successfully immobilized on mitochondria in a reaction-free way by linking C8 alkyl chain on the N atom. This reaction-free immobilization approach efficiently prevents irreversible damage to mitochondrial structure and potential effects on mitochondrial function, as well as photosensitizer leaking from mitochondria during phototherapy. Superoxide anion (O2•-) can be created efficiently under red LED irradiation, which directly damages mitochondria and causes cell death, boosting PDT efficiency. A series of studies demonstrated the great potential of NRNC-8 dyes as efficient mitochondria-targeted imaging-guided photodynamic therapy agents, further highlighting the potential value of the “reaction-free mitochondrion-immobilized” strategy in the design of mitochondria-targeted photosensitizers for more efficient photodynamic therapy.