Metal-drug nanoparticles-mediated osteolytic microenvironment regulation for enhanced radiotherapy of orthotopic osteosarcoma

Osteosarcoma is the most common primary malignant bone tumor with the pathological essence of osteolysis, which seriously reduces the quality of life. To improve the treatment of osteosarcoma, current strategies focus on inhibiting osteolysis and cancer cell growth through combination therapy. Here, we firstly developed a new “carrier free” core-shell metal-drug nanoparticles to enhance the treatment of orthotopic osteosarcoma through inhibiting osteoclast activity and sensitizing radiotherapy. The core was formed by self-assembly of ferric ions with zoledronate (ZOL). The resultant nanoparticles with active pharmaceutical ingredient (API) content over 60 wt% and changeless ingredients of Fe and ZOL can induce efficient cell death and easy for large-scale synthesis. In addition, the inbuilt ZOL and surface modified hyaluronic acid could make the nanoparticles escape skeleton absorption and increase the concentration of zoledronate at the tumor site. Once accumulated in tumor, the released ZOL attenuated osteoclast activity around the tumors to prevent osteolysis. Meanwhile, the free radicals generated efficiently from [email protected] through Fenton-like reaction sensitized radiotherapy to kill the tumor cells. The results corroborated the feasibility of [email protected] mediated synergistic therapy against orthotopic osteosarcoma through sensitized radiotherapy and osteolysis inhibition. Therefore, this facile nanoplatform provides a new combinatorial strategy for treating osteosarcoma and opens a window for the application of metal-drug nanoparticles.