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Molecular design plays a crucial role in regulating the photophysical properties and photodynamic therapy (PDT) performance of photosensitizers (PSs); however, realizing PDT-based synergistic therapy based on sole PSs is still rarely reported. Herein, three near-infrared red type I PSs (named TP1, TP2, and TP3) were synthesized by adjusting their electron acceptors. The results demonstrated that these PSs exhibited aggregation-enhanced reactive oxygen species (ROS) generation efficiency and cyano groups on PSs can reduce ROS generation in solution while achieving efficient PDT-based synergistic therapy in cells via glutathione depletion. [ABSTRACT FROM AUTHOR]

Type I photosensitizers (PSs) with the ability to generate reactive oxygen species (ROS) containing superoxide anion and hydroxyl radical have promising application potential for treating hypoxia tumors, but the deep mechanism of type II ROS converts to the type I ROS in the PSs is still unclear, it is urgent to reveal influencing factors about inducing type I ROS generation. Herein, six PSs with aggregation‐induced emission properties, which were fabricated with the same electronic acceptor but different electronic donors and "π‐bridge", have been successfully prepared to explore the influencing mechanism of generating superoxide anion and hydroxyl radical from organic PSs. Experimental results discovered two factors containing molecular structure and aggregated environment could decide the ROS efficiency and types of PSs. On the level of designing molecular structure, we discovered that "π‐bridge" with a lower energy level of the lowest triplet state could be beneficial for triggering the production of superoxide anion, and electronic donor of triphenylamine was an important factor in producing hydroxyl radical than another donor of dimethylamine. On the level of designing aggregates of PS‐based polymeric nanoparticles, bovine serum albumin could improve largely the generation efficiency of superoxide anion. Due to the satisfactory ROS efficiency and better biocompatibility, synthetic PSs showed excellent photodynamic therapy outcomes in vitro/vivo. [ABSTRACT FROM AUTHOR]

• A new photosensitizer with some better performances of aggregation induced near-infrared red fluorescence and better water solubility is designed and prepared by adopting PEGylation engineering. • Synthetic photosensitizer displays remarkable water solubility (37 µg/mL), and maximal fluorescent wavelength peaks at 670 nm and extends to 850 nm of tail of fluorescent spectrum in aqueous solution. • Synthetic photosensitizer could produce type I/II ROS of singlet oxygen, superoxide anions and hydroxyl radicals with higher efficiency. • Synthetic photosensitizer could label clearly cancer cells, and shows great photodynamic therapy effect for cancer cells under normoxia and hypoxia. Photodynamic therapy has still received more research attention because of its significant advantages of minimally invasive, high selectivity and non-drug-resistance. Photosensitizer is one of important compositions in the photodynamic therapy process, which could be divided into two categories of containing energy transfer dominant process (type II) and electron transfer dominant process (type I) from triplet state to oxygen. Usually, type I photosensitizers have the merit of low oxygen dependence, leading them to become a popular and important candidate for treating cancers because there is hypoxic environment in the solid tumor. However, poor water solubility and short emissive wavelength of reported type I photosensitizer make them suffer certain limitation in clinical application. Hence, it is urgent to develop water-soluble near-infrared red type I photosensitizer. Herein, choosing classical biocompatible macromolecule of polyethylene glycol to modify the designed ionic type I photosensitizer with aggregation-induced near-infrared red fluorescence to prepare a new water-soluble polymeric type I/II photosensitizer (named as PEG-MTPABZ-PyC). PEG-MTPABZ-PyC displays remarkable water solubility (37 µg/mL), and maximal fluorescent wavelength peaks at 670 nm and extends to 850 nm of tail of fluorescent spectrum in aqueous solution, which endows it better efficiency of labelling cells by the significant red fluorescence. Additionally, its superior type I/II reactive oxygen species provide better killing of cancer cells in vitro. This study provides an effective method to prepare water-soluble near-infrared red type I/II photosensitizer, which exhibits satisfactory photophysical property and biocompatibility as well as excellent efficiency for killing cancer cells under normoxia and hypoxia, offering great potential for clinical disease treatment. [ABSTRACT FROM AUTHOR]