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Hypoxia is a common feature of solid tumors and is considered to be the fatal flaw of conventional photodynamic therapy (PDT), which severely reduces the overall therapeutic efficacy. Here, we developed a series of halogenated photosensitizers to address this issue. The results showed that the introduction of heavy atoms enhanced the spin-coupling effect of the photosensitizers and effectively improved the type I PDT (non-oxygen-dependent) efficiency. The preferred iodine-substituted photosensitizer NRh–I was used as the basic architecture, and further nitrosyl modification was performed to obtain the NO small-molecule prodrug, which was finally encapsulated with DSPE-mPEG 5k to obtain a biocompatible NO nanophotocontrolled prodrug. By using the enhanced permeability and retention effect (EPR), the prodrug system can precisely target the lesion site, release a high concentration of NO by photocontrol, kill the tumor cells, and at the same time, cascade with ROS released with the same "time-space" precision to generate higher cytotoxicity, ONOO−, which generates a stronger targeted synergistic therapeutic effect. This "butterfly effect" strategy maximizes the effect of PDT and broadens the idea of translational medicine. [Display omitted] • Heavy atoms enhanced type I photosensitizer reactions. • Preferably NRh-I was modified into NO prodrug. • NO cascaded with ROS to form the more toxic ONOO-. • Liposome delivery increased drug delivery concentration. [ABSTRACT FROM AUTHOR]

This study was the first to investigate the synthesis of near-infrared light-sensitive NO prodrug [Mn(PaPy2Q)(NO)]ClO 4 , and detection the amount of NO released by the drug in different time and near infrared light (10 mW, 20 mW). It showed that with the increase of light power, the time required for the drug to release NO was shortened, and we selected 20 mW, 10 min as a follow-up study of light power and irradiation time while ensuring the near-infrared light did not affect tumor cells. The cells were irradiated with 20 mW of near-infrared light for 10 min at 6 h after treatment with the drug on PC-3, LNCaP and 22RV1 cells, and NO concentration and cell survival rate were tested at 12 h, 24 h and 48 h. Experiments showed that NO concentration remained stable within 48 h and [Mn(PaPy2Q)(NO)]ClO 4 inhibited the proliferation of cells in a concentration and time-dependent manner. Then we also found that [Mn(PaPy2Q)(NO)]ClO 4 increased the expression of apoptosis-related proteins (PARP, Bax, Caspase 3/9), inhibited the expression of BCl-2 and increased the activity level of Caspase 3/7, which showed [Mn(PaPy2Q)(NO)]ClO 4 promoted prostate cancer cells apoptosis. Next, the results in xenograft mouse model showed that [Mn(PaPy2Q)(NO)]ClO 4 also had anti-prostate cancer effects in vivo, and the NO concentration increased in the tumor after near-infrared light irradiation. After [Mn(PaPy2Q)(NO)]ClO 4 treatment 6 weeks, tumor volume was significantly reduced, Ki67 and BrdU protein expression was significantly reduced. TUNEL assay results showed that [Mn(PaPy2Q)(NO)]ClO 4 could promote the apoptosis of solid tumors in vivo and in a concentration-dependent manner. [Display omitted] • The NO prodrug inhibited the proliferation of PCa cells in a dose and time-dependent manner and induced apoptosis. • The NO prodrug could release high concentration NO by NIR in PCa cells. • The light-activated NO prodrug had anti-PCa effects in vivo. [ABSTRACT FROM AUTHOR]