Cobalt carbonate nanorods enhance chemotherapy via neutralization of acidic tumor microenvironment and generation of carbonate radical anions for necrosis

Abstract

One of the hallmarks of cancer is the acidic extracellular space surrounding the tumor, which is linked to metabolic reprogramming and the use of glycolysis. Additionally, the acidic tumor microenvironment (TME) establishes a physiological barrier called "ion trapping" and significantly lowers the ability of cells to absorb weak-base chemotherapy agents. Although CO₃^2- containing agents and nanoformulations could effectively neutralize the tumor acidity, the CO₃^2- based therapeutic effect was insufficiently investigated. Herein, we fabricated cobalt carbonate (CoCO₃) nanorods as drug carriers with acidity-responsive dissociation and acidity neutralization properties for the loading of hydrophobic and weak-basic drugs, evodiamine (EVO). After effective surface modification, CoCO₃-PEG-EVO could effectively accumulate in the tumor and inhibit the growth of the tumor. On the one hand, acidity neutralization of CoCO₃-PEG-EVO could lead to the ion trapping overcome and cellular uptake of EVO enhancement for effective cancer cell apoptosis. On the other hand, the high level of H₂O₂ in the tumor and HCO₃^- from dissociated CoCO₃-PEG-EVO could cause the generation of CO₃·^- through a Fenton-like reaction while not hydroxyl radical (·OH) for cancer cell necrosis. Our results thus point to a potent yet easily prepared CoCO₃ nanosystem (CoCO₃-PEG-EVO) to induce cancer cell death, and because of its well-defined composition and excellent biocompatibility, it may be used in clinical settings in the future.