Photodynamic therapy (PDT) is an effective tumor treatment modality that uses light-activating photosensitizing drugs known as photosensitizers (PSs). PSs selectively accumulate in tumor tissues and convert molecular oxygen in cells and tissues into biotoxic reactive oxygen species (ROS) under specific wavelengths of light irradiation, resulting in oxidative damage to cancer cells. PDT is noninvasive and has low toxicity. It has attracted widespread attention in tumor treatment research. However, there are still challenges in the use of PDT for the treatment of tumors. First, the tissue penetration depth of light is insufficient, which reduces the PDT effect in deep tumor tissue. Second, PDT has poor targeting ability and can easily cause damage to normal tissues. Third, the tumor tissue can scavenge the generated ROS, reducing the therapeutic efficiency of PDT.Compared with normal tissue, tumor tissue has significant pathological changes, showing a characteristic tumor microenvironment, such as weak acidity, hypoxia, protease overexpression, and glutathione (GSH) overexpression. In the design of PSs, overexpressed GSH in the tumor microenvironment is used as a biotarget and trigger factor that can selectively activate the photodynamic activity of PSs accumulated at tumor sites. Therefore, PDT-targeted treatment of tumors can be achieved, and damage to normal tissues can be reduced. However, overexpression of GSH also consumes ROS generated by PS irradiation, which seriously affects the therapeutic efficiency of PSs in tumor phototherapy. In this review, the roles of GSH in organisms are introduced, and GSH-activating and GSH-depleting PSs that have appeared in recent years are described. Finally, the challenges and future development directions of GSH-responsive PSs are discussed.
Activated PSs are only selectively activated in tumors for PDT and have less nonspecific phototoxicity. Under light irradiation, the activable PS maintains quenching in nontumor tissues, produces only a small amount of ROS, and has low tissue toxicity. However, when PSs are activated by specific tumor microenvironmental biological targets, the ROS production capacity can be significantly improved to achieve in situ targeted therapy of tumors. The concentration of GSH at the tumor site is much higher than that in normal cells and extracellular fluid, making GSH an excellent PS trigger. Using GSH as an endogenous stimulator to activate PSs to trigger photodynamic responses at tumor sites selectively can improve the precision of PDT and tumor treatment efficiency and reduce toxic side effects on normal tissues.The design principle of GSH-activated PSs is mainly to regulate the ROS production capacity of the PS through fluorescence resonance energy transfer (FRET) or intramolecular photoelectron transfer (PeT). The disulfide bond (S—S) is broken by the attack of reduced GSH, which can be used as a bonding group to connect the donor and acceptor molecules covalently to achieve intramolecular FRET. The disulfide bond can be used as a linking group to connect the PS molecule with the PDT quencher and realize the selective activation of the PS at high concentrations of GSH in tumor tissue. The introduction of electron donors or acceptors into the molecule to form a PeT system with a chromophore can control the ROS generation capacity of the PSs. 2,4-dinitrobenzenesulfonate (DNBS) is often used as a photodynamic quenching group because of its strong electron absorption ability. The excited state of the PS is quenched by introducing the DNBS group, and the singlet oxygen generation ability is then quenched. Before the PS is activated, it does not exhibit cytotoxicity. After the sulfonyl group in DNBS is cleaved under the induction of GSH, the DNBS group leaves, and the PS is activated, which can generate cytotoxic singlet oxygen. In addition, azo ligands and nitro groups are often used to design GSH-responsive PSs.The high expression of GSH in tumor cells can eliminate exogenous ROS, which is not conducive to the accumulation of exogenous ROS and reduces the efficiency of PDT treatment. Currently, the most common method used to consume GSH is the use of disulfide and highly oxidized metal ions, including manganese (Ⅲ), iron (Ⅲ), and copper (Ⅱ) ions. High-oxidation-state metal ions can consume GSH through redox reactions, and the metal ions themselves are reduced to low-oxidation-state metal ions. The introduction of disulfide bonds and highly oxidized metal ions into PSs can effectively reduce the GSH concentration and improve the therapeutic effect of PDT.
GSH-activated PSs can be selectively turned on at tumor sites, improving the accuracy of PDT and tumor treatment efficiency and reducing side effects on normal tissues. The consumption of GSH not only solves the problem of ROS scavenging and improves PDT efficacy but also reduces the drug resistance of tumors and improves the therapeutic effect. Although research on GSH-responsive PSs has made significant progress recently, some problems and challenges remain. First, the exact role of GSH in multiple tumors and different tumor stages must be elucidated. Second, GSH deletion leads to the upregulation of related GSH synthetase, potentially negatively affecting tumor therapy. Finally, how to fundamentally inhibit GSH synthesis remains to be studied.
