Ion drugs for precise orthotopic tumor management by <i>in situ</i> the generation of toxic ion and drug pools

Abstract

<b>Background:</b> Asymmetric intracellular and extracellular ionic gradients are critical to the survivability of mammalian cells. Given the importance of manganese (Mn²⁺), calcium (Ca²⁺), and bicarbonate (HCO₃^-) ions, any alteration of the ion-content balance could induce a series of cellular responses. HCO₃^- plays an indispensable role for Mn-mediated Fenton-like reaction, but this is difficult to achieve because bicarbonates are tightly regulated by live cells, and are limited in anticancer efficacy. <b>Methods:</b> A responsive and biodegradable biomineral, Mn-doped calcium carbonate integrated with dexamethasone phosphate (DEX) (Mn:CaCO₃-DEX), was reported to enable synergistic amplification of tumor oxidative stress, reduce inflammation, and induce Ca-overload cell apoptosis by elevating the intracellular and extracellular ionic gradients. <b>Results:</b> Under the acidic environment in tumor region, the ions (Mn²⁺, CO₃^2-, Ca²⁺) were released by the degradation of Mn:CaCO₃-DEX and then escalated oxidative stresses by triggering a HCO₃^--indispensable Mn-based Fenton-like reaction and breaking Ca²⁺ ion homeostasis to cause oxidative stress in cells and calcification. The released anti-inflammatory and antitumor drug, DEX, could alleviate the inflammatory environment. The investigations <i>in vitro</i> and <i>in vivo</i> demonstrated that the synergistic oncotherapy could effectively inhibit the growth of subcutaneous tumors and orthotopic liver tumors. Notably, normal cells showed greater tolerance of the synergistic influences. <b>Conclusion:</b> As an ion drug, Mn:CaCO₃-DEX is an excellent potential diagnostic agent for precise orthotopic tumor management by the generation <i>in situ</i> of toxic ion and drug pools in the environment of tumor region, with synergistic effects of enhanced chemodynamic therapy, calcification, and anti-inflammation effects.