Specific Generation of Singlet Oxygen through the Russell Mechanism in Hypoxic Tumors and GSH Depletion by Cu‐TCPP Nanosheets for Cancer Therapy

Abstract

The generation of singlet oxygen ( 1 O 2 )d uring photodynamic therapyi sl imited by the precise cooperation of light, photosensitizer,a nd oxygen, and the therapeutic efficiency is restricted by the elevated glutathione (GSH) levels in cancer cells.H erein, we report that an ultrathin twodimensional metal-organic framework of Cu-TCPP nanosheets (TCPP = tetrakis(4-carboxyphenyl)porphyrin) can selectively generate 1 O 2 in at umor microenvironment. This process is based on the peroxidation of the TCPP ligand by acidic H 2 O 2 followed by reduction to peroxylr adicals under the action of the peroxidase-like nanosheets and Cu 2+ ,and their spontaneous recombination reaction by the Russell mechanism. In addition, the nanosheets can also deplete GSH. Consequently,the Cu-TCPP nanosheets can selectively destroy tumor cells with high efficiency,constituting an attractive way to overcome current limitations of photodynamic therapy.

Enhancement of tumor lethality of ROS in photodynamic therapy

“…Studies have found that there are abundant anti‐oxidants in tumor tissues, especially the overexpression of glutathione (GSH). GSH neutralizes the ROS produced by PDT and, thus, weakens the killing effect of ROS on tumors, greatly reducing the anti‐tumor efficiency of ROS 87–89 . The researchers realized the importance of inhibiting the ROS defense system in the PDT process, so they developed a strategy to reduce GSH in tumor tissues to enhance the ROS killing effect, and opened a new path for improving the efficacy of PDT.…”

“…At present, the commonly used GSH removal strategies are mainly Cu, 89 Mn, 92 Fe, 93 or Au 94 meta‐elements. However, excessive use of these metals may produce serious side effects such as systemic toxicity, which affects the conversion of GSH removal strategies to clinical 95,96 .…”

“…GSH neutralizes the ROS produced by PDT and, thus, weakens the killing effect of ROS on tumors, greatly reducing the anti-tumor efficiency of ROS. [87][88][89] The researchers realized the importance of inhibiting the ROS defense system in the PDT process, so they developed a strategy to reduce GSH in tumor tissues to enhance the ROS killing effect, and opened a new path for improving the efficacy of PDT. According to reports, copper and GSH can react through metal reduction and promote the pro-oxidant effect.…”

“…Furthermore, the product of the redox reaction can also catalyze the production of more ROS, which further enhances the killing effect of ROS on tumors during the treatment process. At present, the commonly used GSH removal strategies are mainly Cu, 89 Mn, 92 Fe, 93 or Au 94 meta-elements. However, excessive use of these metals may produce serious side effects such as systemic toxicity, which affects the conversion of GSH removal strategies to clinical.…”

Amplified Antitumor Efficacy By A Targeted Drugs Retention and Chemosensitization Strategies-Based “Combo” Nanoagent Together With PD-L1 Blockade In Reversing Multidrug Resistance

“…Besides, a GSH consumption strategy was simultaneously performed in this study. An increasing amount of evidence has suggested that CuTCPP, consisting of Cu 2+ and tetrakis(4-carboxyphenyl)porphyrin (TCPP) ligands, has a distinct GSH scavenging effect through the cycle conversion of Cu 2+ into Cu 1+ in CuTCPP [29][30][31]. Thus, CuTCPP was encapsulated into the core of poly(lactic acid-co-glycol acid) (PLGA)based NPs to sensitize cancer cells to chemotherapy, the so-called chemosensitization, via Cu 2+ -induced GSH depletion along with a pro-oxidant [32].…”