Novel intravenous formulation for radiosensitization in osteosarcoma treatment.

Osteosarcoma (OS) is the most common primary malignant bone tumor in children and adolescents. While radiotherapy is an adjuvant treatment option for OS, particularly in cases of unresectable recurrent metastases, its efficacy remains limited. Enhancing radiosensitivity in OS cells is therefore crucial for improving treatment outcomes. Hafnium oxide, a known radiosensitizer, has demonstrated potential but its current formulation restricts its use to intratumoral administration, posing challenges for treating intraosseous tumors. The development of an intravenous formulation is thus highly desirable. Furthermore, radiotherapy resistance, driven by tumor hypoxia and an immunosuppressive microenvironment, further compromises its effectiveness. In this study, we synthesized hafnium-doped Prussian blue nanoparticles (HP) coated with a tannic acid-manganese metallophenol network (HPTM) to improve biocompatibility and enable intravenous administration. Following intravenous injection in a murine model of OS tibialis in situ tumors with lung metastases, HPTM effectively localized to the primary tumor. Within the acidic tumor microenvironment, manganese was released, activating the STING pathway and triggering anti-tumor immune responses. Moreover, near-infrared light irradiation of the Prussian blue component induced a photothermal effect, promoting apoptosis. Concurrently, under low-dose X-ray irradiation, HPTM augmented radiation energy deposition, generating reactive oxygen species and inducing DNA damage in tumor cells. This synergistic therapeutic approach significantly increased apoptosis in radiotherapy-resistant OS cells, reduced lung metastases, and suppressed primary tumor growth. These findings suggest a promising avenue for clinical translation, integrating radiosensitization, photothermal therapy, and STING pathway activation to overcome current limitations in OS radiotherapy.