Glutathione-responsive copper-disulfiram nanoparticles for enhanced tumor chemotherapy
Disulfiram (DSF), a familiar FDA-approved drug used for alcohol withdrawal , has recently been verified with potent antitumor therapeutic effect by generating Cu(DTC) 2 , which is the complex of its metabolite diethyldithiocarbamate (DTC) and copper. However, its poor tumor selectivity and insufficient endogenous Cu 2+ concentration within tumor site largely hinders the application of DSF-based antitumor therapy. Therefore, a GSH-responsive coordination nanoparticles ( [email protected] ) was established as a copper carrier to achieve synchronous but separate delivery of Cu 2+ and DSF without antitumor ability, further to realize selectively triggered tumor in situ Cu(DTC) 2 generation for antitumor therapy. A widely-used proteasome inhibitor ixazomib (IXZ) was chosen as ligands and Cu 2+ was used as coordination nodes to form nanosized [email protected] The DSF encapsulated in [email protected] could be reduced to DTC by intracellular GSH, which could contend for Cu 2+ and realize in situ high toxic Cu(DTC) 2 generation. Meanwhile, the chelation could lead to the disassembly of [email protected] and release of IXZ to eventually achieve tumor specific “transformation from low toxicity to high toxicity” chemotherapy. The results of in vitro and in vivo experiments demonstrated that the as-prepared nanoplatform [email protected] showed good biosafety and excellent antitumor effect via endoplasmic reticulum stress (ERS) as well as reactive oxygen species (ROS) generation pathway. Therefore, this nanocarrier provides an inspiring strategy with specific-triggered antitumor Cu(DTC) 2 generation for DSF-based chemotherapy with high therapeutic effect and biosafety and showing great potential of treating cancer.
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