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.

中文翻译：

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含藤黄酸和钙纳米线的 pH 响应性水凝胶促进骨肉瘤线粒体凋亡


钙 （Ca2+） 超负荷治疗在肿瘤学中受到广泛关注。然而，由于肿瘤部位 Ca2+ 积累不足和细胞内 Ca2+ 内流不理想，其治疗效果仍然有限。在这项研究中，藤黄酸 （GA） 是一种已知可促进 Ca2+ 内流的天然酚类化合物，被封装在含有 Ca2+ 磷酸氢纳米线 （CHP） 的酶触发、pH 响应性水凝胶 （GM@Lip@CHP-Gel） 中，以实现骨肿瘤治疗的协同方法。GM@Lip@CHP-Gel 选择性地响应微酸性肿瘤微环境，触发其 3D 网络结构的降解并维持 GA 和 Ca2+ 释放到肿瘤细胞中。GA 随后刺激肿瘤细胞中的 Ca2+ 内流，有效破坏 Ca2+ 稳态。CHP 纳米线作为连续的 Ca2 + 来源，增强 GA 介导的 Ca2 + 过载并促进肿瘤细胞中的线粒体凋亡。联合策略导致体内肿瘤抑制率为 79 %，肺转移抑制率为 89.4 %，对骨组织具有保护作用。这种天然来源的 Ca2+ 介导的治疗在生理环境中表现出理化稳定性，并最大限度地减少了对健康器官的副作用，使其成为临床骨癌治疗的有前途的方法。