pH-responsive hydrogel with gambogic acid and calcium nanowires for promoting mitochondrial apoptosis in osteosarcoma

Calcium (Ca2+) overload therapy gained significant attention in oncology. However, its therapeutic efficacy remained limited due to insufficient Ca2+ accumulation at the tumor site and suboptimal intracellular Ca2+ influx. In this study, gambogic acid (GA), a natural phenolic compound known to promote Ca2+ influx, was encapsulated within an enzyme-triggered, pH-responsive hydrogel (GM@Lip@CHP-Gel) containing Ca2+ hydrogen phosphate nanowires (CHP) to achieve a synergistic approach for bone tumor therapy. GM@Lip@CHP-Gel selectively responded to the slightly acidic tumor microenvironment, triggering degradation of its 3D network structure and sustaining the release of GA and Ca2+ into tumor cells. GA subsequently stimulated Ca2+ influx in tumor cells, effectively disrupting Ca2+ homeostasis. CHP nanowires served as a continuous Ca2+ source, enhancing GA-mediated Ca2+ overload and promoting mitochondrial apoptosis in tumor cells. The combined strategy resulted in an in vivo tumor suppression rate of 79 % and a lung metastasis inhibition rate of 89.4 %, with a protective effect on bone tissue. The naturally derived, Ca2+-mediated treatment demonstrated physiochemical stability in physiological environments and minimized side effects on healthy organs, positioning it as a promising approach for clinical bone cancer therapy. The therapeutic process of GM@Lip@CHP-Gel. Nano-sized GM@Lip were loaded into fibrin sol containing Ca2+ hydrogen phosphate nanowires (CHP) and injected locally into bone tumor sites of mice. Fibrin hydrogels were formed under physiological conditions when acting with thrombin in vivo. Within the acidic tumor microenvironment (TME), CHP underwent gradual degradation, thereby releasing Ca2+ progressively into the tumor region. Concurrently, the liberated GA facilitated Ca2+ ingress into tumor cells, consequently disrupting the intracellular Ca2+ equilibrium. GA enhanced cellular Ca2+ overload triggered mitochondrial dysfunction as well as oxidative stress and thereby induced cell apoptosis, which blocked the proliferation, migration and invasion of tumor cells, eventually achieving tumor shrinkage and metastasis prevention. [Display omitted]