pH-Regulating Nanoplatform for the “Double Channel Chase ” of Tumor Cells by the Synergistic Cascade between Chlorine Treatment and Methionine-Depletion Starvation Therapy

Abstract

During rapid proliferation and metabolism, tumor cells show a high dependence on methionine. The deficiency of methionine exhibits significant inhibition on tumor growth, which provides a potential therapeutic target in tumor therapy. Herein, ClO 2 -loaded nanoparticles (fluvastatin sodium&metformin&bupivacaine&ClO 2 @CaSiO 3 @MnO 2 -arginine-glycine-aspatic acid (RGD) (MFBC@CMR) NPs) were prepared for synergistic chlorine treatment and methionine-depletion starvation therapy. After outer layer MnO 2 was degraded in the high glutathione (GSH) tumor microenvironment (TME), MFBC@CMR NPs released metformin (Me) to target the mitochondria, thus interfering with the tricarboxylic acid (TCA) cycle and promoting the production of lactate. In addition, released fluvastatin sodium (Flu) by the NPs acted on monocarboxylic acid transporter 4 (MCT4) in the cell membrane to inhibit lactate leakage and induce a decrease of intracellular pH, further prompting the NPs to release chlorine dioxide (ClO 2 ), which then oxidized methionine, inhibited tumor growth, and produced large numbers of Cl − in the cytoplasm. Cl − could enter mitochondria through the voltage-dependent anion channel (VDAC) channel, which was opened by bupivacaine (Bup). The disruption of Cl − homeostasis promotes mitochondrial damage and membrane potential decline, leading to the release of cytochrome C (Cyt-C) and apoptosis inducing factor (AIF) and further inducing cell apoptosis. To sum up, the pH-regulating and ClO 2 -loaded MFBC@CMR nanoplatform can achieve cascade chlorine treatment and methionine-depletion starvation therapy toward tumor cells, which is of great significance for improving the clinical tumor treatment effect.

Ion Interference Therapy of Tumors Based on Inorganic Nanoparticles

“…Meanwhile, Yuping Jiang et al prepared a ClO 2 -loaded CaSiO 3 nanoparticle which can produce large numbers of Cl − by capturing methionine to disturb the balance of homeostasis in cancer cells ( Figure 5 ). The released Cl − by ClO 2 , which can enter the mitochondria through the voltage-dependent anion channel (VDAC), leads to mitochondrial damage and membrane potential decline, which further induce cell apoptosis [ 41 ]. In general, chloride ions directly or indirectly affect the ion homeostasis at different organelle levels in cells, including the endoplasmic reticulum, lysosome and mitochondria, thus affecting cell activity.…”

Selective Methionine Pool Exhaustion Mediated by a Sequential Positioned MOF Nanotransformer for Intense Cancer Immunotherapy

“…Relevant tactics mainly cover dietary restriction, administration of inhibitor of system transporters or oxidation of methionine by enzyme and oxychloride. [11][12][13][14][15][16] Although promising, these strategies still have several disadvantages on selectivity and safety. First, small molecule inhibitors have been limited in cell permeability and need high dose administration.…”