Ca²⁺-Overload-Mediated Ca²⁺/Chemo Synergetic Cancer Therapy

Although rapid advances in nanotechnology have contributed greatly to achievements in cancer treatment,both the in vivo cytotoxicity and the biosecurity of nanoparticles have been sources of controversy.The unpredictable biological risks and side effects brought by nanoparticles inevitably to patients have greatly hindered the development and transformation of nanomedicine from theoretical experiment to clinical application.Therefore,new direction of nanomedicine is urgently needed to break this dilemma.Recently,the strategy of using Ca²⁺ for tumor treatment has attracted much attention due to its high biological safety and therapeutic effect.Not only are the Ca²⁺ involved in cancer treatment abundant and biosafety in the body,but also cancer cells are more susceptible to Ca²⁺ than normal cells,making them a potentially therapeutic ion with controllable side effects.Herein,based on Ca²⁺ overload and supplemented by the synergistic effect of multiple therapies,we constructed a new nanomedicine platform with high safety and high efficacy to achieve the ideal nanomedicine for cancer with better efficacy and lower side effects.In this study,hydroxyapatite nanorods?NHA?were used as the carrier,wrapped with hyaluronic acid?HA?,modified with glucose oxidase?GOx?and loaded with doxorubicin?DOX?to construct HNHA-GD nanoplatform.Under the targeting effect of the surface HA,the nanoparticles will actively accumulate in the tumor site and the GOx modified in the HNHA-GD will catalyze the intracellular glucose into gluconic acid and hydrogen peroxide?H₂O₂?with the effect of starvation treatment.On the one hand,the produced gluconic acid then can promote the decomposition of HNHA-GD and release a large number of Ca²⁺ together with the generated H₂O₂ to induce intracellular Ca²⁺ overload.On the other hand,it can also promote the massive release of the surface-loaded DOX in HNHA-GD,which not only plays the role of chemotherapy,but also increases the intracellular Ca²⁺ concentration promoting the aforementioned intracellular Ca²⁺ overload.Therefore,Ca²⁺/Chemo synergistic anticancer therapy based on Ca²⁺ overload can be achieved.It can be verified by in vitro experiments that this nanoparticle causes 78.8% cell apoptosis for MCF-7 cancer cell under the 40 ?g/m L concentration,and the lethal mechanism is closely related to intracellular Ca²⁺ concentration.This Ca²⁺/Chemo synergistic therapy based on Ca²⁺ overload is expected to be a new potential Ca²⁺ anticancer strategy,providing a new way forward for the future development of nanomedicine.