Acidity ‐Responsive Nanoreactors Destructed “Warburg Effect” for Toxic‐Acidosis and Starvation Synergistic Therapy

A  therapeutic strategy is designed to destruct the “Warburg Effect” by breaking tumor cells’ malignant pursuit of energy and maintenance of cytoplasmic alkalinization. The combination of homeostasis disruption and metabolic blockade strategy based on the Warburg effect destruction and autophag y inhibition is expected to provide a new perspective for tumor therapy. Abstract“Warburg Effect” shows that most tumor cells rely on aerobic glycolysis for energy supply, leading to malignant energy deprivation and an “internal alkaline external acid” tumor microenvironment. Destructing the “Warburg Effect” is an effective approach to inhibit tumor progression. Here in, an acidity-responsive nanoreactor (Au@CaP-Flu@HA) is fabricated for toxic acidosis and starvation synergistic therapy. In the nanoreactor, the fluvastatin (Flu) could reduce lactate efflux by inhibiting the lactate-proton transporter (monocarboxylate transporters, MCT4), resulting in intracellul ar lactate accumulation. Meanwhile, the glucose oxidase-mimic Au-nanocomposite consumes glucose to induce cell starvation accompanied by gluconic acid production, coupling with lactate to exacerbate toxic acidosis. Also, the up-regulated autophagic energy supply of tumor cells under energy deprivati on and hypoxia aggravation is blocked by autophagy inhibitor CaP. Cellular dysfunction under pHi acidification and impaired Adenosine Triphosphate (ATP) synthesis under starvation synergistically promote tumor cel...
Source: Small - Category: Nanotechnology Authors: Tags: Research Article Source Type: research