Killing cancer cells by delivering a nanoreactor for inhibition of catalase and catalytically enhancing intracellular levels of ROS
Journal
RSC Advances
Journal Volume
5
Journal Issue
105
Pages
86072-86081
Date Issued
2015
Author(s)
Abstract
Intracellular hydrogen peroxide levels have the potential to be exploited in cancer therapy. We have synthesized uniform and size-controlled copper-impregnated mesoporous silica nanoparticles (Cu-MSN) containing a catalase inhibitor, 3-amino-1,2,4-triazole (AT) for ROS-mediated apoptosis in cancer cells. Copper species in the framework and aminotriazole loading were confirmed by electron spin resonance (ESR) and nuclear magnetic resonance (NMR) spectroscopies, respectively. The metal-ligand binding between the copper and AT are sensitive to the endosomal environment (pH = 5.5) for the release of AT to inhibit cytosolic catalase activity. The subsequent enhanced level of intracellular hydrogen peroxide, after catalase inhibition, is transformed into toxic, reactive oxygen species (ROS) by the catalysis of Cu(ii) on MSN. The intracellularly delivered Cu-MSN-AT exhibited significant activity against colon carcinoma (HT-29 cell line) substantiated by increased levels of ROS, where AT drove up the hydrogen peroxide concentration and also the level of free radicals through a Fenton-like reaction. The trigger of cell apoptosis was induced from ROS attack to lipid membranes in order for further radical propagation to cause lipid peroxidation and eventually, a decrease in the membrane fluidity and mitochondrial membrane potential. As a result, an increase in the membrane permeability caused the release of cytochrome c into the cytoplasm and further activation of apoptotic cascades to trigger DNA fragmentation. The design of the Cu-MSN-AT system takes advantage of a synergistic effect to inhibit antioxidant defenses and catalyze the activation of lethal ROS by the framework of copper ions to kill cancer cells which represents a novel chemotherapeutic strategy for ameliorating the toxic side effects from non-specific ROS generation in traditional chemotherapeutic agents. ? The Royal Society of Chemistry 2015.
SDGs
Other Subjects
Cell culture; Cell death; Cell membranes; Chemical activation; Copper; Cytology; Diseases; Electron spin resonance spectroscopy; Free radicals; Hydrogen peroxide; Lipids; Magnetic moments; Metal ions; Mitochondria; Nuclear magnetic resonance; Nuclear magnetic resonance spectroscopy; Oxidation; Peroxides; Synthesis (chemical); Chemotherapeutic agents; Fenton-like reactions; Hydrogen peroxide concentration; Membrane permeability; Mesoporous silica nanoparticles; Mitochondrial membrane potential; Nuclear magnetic resonance(NMR); Reactive oxygen species; Cells
Type
journal article