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

Abstract

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.

Versatile Electrochemical Biosensor Based on the Target-Controlled Capture and Release of DNA Nanotubes for the Ultrasensitive Detection of Multiplexed Biomarkers

“…Bioactive molecules such as proteins, − microRNAs (miRNAs), − and peptides, , as indispensable components of cells and tissues, play a crucial role in cell proliferation, tissue differentiation, and body metabolism. Studies have found that tumor progression and prognosis are accompanied by abnormal changes in the expression levels of more than one bioactive substance. − For example, miRNAs are important regulators of most physiological processes, and their dysregulated expressions are related to cancer and other pathological diseases. − Meanwhile, glutathione (GSH), as one of the most plentiful endogenous antioxidants against free radicals and toxins, has been shown to be significantly upregulated in various cancer cells. − So far, various strategies have been reported for miRNA or GSH detection, such as CRISPR systems, colorimetry, the quantitative polymerase chain reaction, and fluorescence. − However, these existing methods are usually restricted to the analysis of a single biomarker or the same type of different biomarkers, which could no longer meet the growing demand for the early ultrasensitive clinical diagnosis of cancer. Therefore, it is of great significance to develop an ultrasensitive biosensor to monitor different types of biomarkers and further provide more precise and comprehensive data guidance for cancer diagnosis and clinical decision making.…”

Boosting Chemodynamic Therapy by Tumor-Targeting and Cellular Redox Homeostasis-Disrupting Nanoparticles

“…For in vivo fluorescence imaging, the MCF-7 tumor-bearing BALB/c nude mice were injected with NIR797 MIP and NIR797 NIP via the tail vein (for each group, n = 4). The fluorescence imaging measurement was conducted at different time points (2,6,12,24,48, and 72 h). Next, the excised organs and tumor tissues were obtained after the mice were euthanized at 72 h postinjection for further ex vivo imaging and ROI analysis.…”

“…Compared with other therapeutic strategies, CDT possesses multiple outstanding advantages, including high tumor specificity, less limitation on therapeutic depth, and no need for external stimulation . Nevertheless, accumulating evidence has indicated that the CDT efficiency is severely restricted by abnormal redox homeostasis in tumor cells. − Specifically, due to the aberrant metabolism of tumor tissues, elevated H 2 O 2 is produced (ranging from 0.1 to 1 mM) . To balance such oxidative stress, tumor cells have developed unique redox buffer systems, in which glutathione (GSH; 2–10 mM), a typical endogenous antioxidant, is upregulated.…”

Perspectives of metal-organic framework nanosystem to overcome tumor drug resistance

“…The rapid development of bioimaging technology has contributed significantly to exploring the pathological characteristics and metabolic functions of biological tissues by providing vital equipment, which has greatly facilitated the diagnosis of diseases. More recently, MOF-based nanocomposites have been widely used in fluorescence imaging (FL), computed tomography (CT), and magnetic resonance imaging (MRI), as well as [96] . Reproduced with permission from ref [96] .…”