NIR-absorbing Superoxide Radical and Hyperthermia Photogenerator Via Twisted Donor-Acceptor-donor Molecular Rotation for Hypoxic Tumor Eradication

Hypoxia severely impedes the therapeutic efficacies of tumor chemotherapy, radiotherapy and conventional photodynamic therapy (type II PDT). Herein, we proposed a nonplanar near-infrared (NIR)-absorbing hyperthermia and superoxide radical (O2−•) photogenerator (TB) against hypoxic tumors. TB particularly possessed a favorable O2−• generation capability under 808 nm laser irradiation with the donor-acceptor-donor (D-A-D) molecular structure. Moreover, owing to molecular rotation, potent hyperthermia was realized under continuous laser irradiation. For the usage of hypoxic tumor treatment, TB was encapsulated by a block copolymer, poly(ethylene glycol)-b-poly(latic acid) (PEG45-b-PLA24), to fabricate phototheranostic nanoparticles (TB NPs). Due to the twisted molecular structure and the shielding effect of long alkyl chains, the π-π stacking-induced quenching of O2−• could be reduced after the fabrication of nano-assemblies. Significantly, TB NPs exhibited satisfactory O2−• generation for type I PDT and a simultaneously distinct photothermal conversion efficiency (PCE, 62%) for photothermal therapy (PTT) to combat hypoxic tumor cells. Moreover, the high PCE endowed TB NPs with high performance photoacoustic (PA) and photothermal imaging capability. In vivo experiments demonstrated that TB NPs possessed an outstanding phototherapeutic efficacy for eradicating hypoxic tumors. This study established a novel approach for constructing oxygen-independent phototherapeutic reagent against hypoxic tumors .