Copper-Based Metal-Organic Framework Overcomes Cancer Chemoresistance through Systemically Disrupting Dynamically Balanced Cellular Redox Homeostasis.

Chemodrug resistance is a major reason accounting for tumor recurrence. Given the mechanistic complexity of chemodrug resistance, molecular inhibitors and targeting drugs often fail to eliminate drug-resistant cancer cells, and sometimes even promote chemoresistance by activating alternative pathways. Here, by exploiting biochemical fragility of high-level but dynamically balanced cellular redox homeostasis in drug-resistant cancer cells, we design a nanosized copper/catechol-based metal-organic framework (CuHPT) that effectively disturbs this homeostasis tilting the balance toward oxidative stress. Within drug-resistant cells, CuHPT starts disassembly that is triggered by persistent consumption of cellular glutathione (GSH). CuHPT disassembly simultaneously releases two structural elements: catechol ligands and reductive copper ions (Cu+). Both of them cooperatively function to amplify the production of intracellular radical oxidative species (ROS) via auto-oxidation and Fenton-like reactions through exhausting GSH. By drastically heightening cellular oxidative stress, CuHPT exhibits selective and potent cytotoxicity to multiple drug-resistant cancer cells. Importantly, CuHPT effectively inhibits in vivo drug-resistant tumor growth and doubles the survival time of tumor-bearing mice. Thus, along with CuHPT's good biocompatibility, our biochemical, cell biological, preclinical animal model data provide compelling evidence supporting the notion that this copper-based MOF is a predesigned smart therapeutic against drug-resistant cancers through precisely deconstructing their redox homeostasis.

Gold nanoparticles-embedded ceria with enhanced antioxidant activities for treating inflammatory bowel disease.

The excessive reactive oxygen species (ROS) is a hallmark associated with the initiation and progression of inflammatory bowel disease (IBD), which execrably form a vicious cycle of ROS and inflammation to continually promote disease progression. Here, the gold nanoparticles-embedded ceria nanoparticles (Au/CeO2) with enhanced antioxidant activities are designed to block this cycle reaction for treating IBD by scavenging overproduced ROS. The Au/CeO2 with core-shell and porous structure exhibits significantly higher enzymatic catalytic activities compared with commercial ceria nanoparticles, likely due to the effective exposure of catalytic sites, higher content of Ce (III) and oxygen vacancy, and accelerated reduction from Ce (IV) to Ce (III). Being coated with negatively-charged hyaluronic acid, the Au/CeO2@HA facilitates accumulation in inflamed colon tissues via oral administration, reduces pro-inflammatory cytokines, and effectively alleviates colon injury in colitis mice. Overall, the Au/CeO2@HA with good biocompatibility is a promising nano-therapeutic for treating IBD.