Title: Gallium- and Niobium Doped Bioactive Glass: A synergistic approach for cancer-targeted therapy and enhanced bone regeneration

Abstract

Conventional treatments for osteosarcoma focus primarily on eliminating cancer cells, often ignoring the need to promote local bone regeneration, and even hindering this process. This is due to a lack of precise control over target cells, resulting in treatment affecting both normal and cancer cells. To address these limitations, we developed bioactive glasses derived from the 45S5 composition doped with gallium and niobium (BGGN). This multifunctional system synergistically combines the effects of these elements to enhance bone regeneration while treating bone cancer. Our results show that bioactive glasses containing 3 mol% gallium oxide selectively kill human osteosarcoma cells while exhibiting excellent in vivo osteointegration and no local or systemic toxicity. Cell culture media conditioned with the ionic product from the BGGN glass was able to eliminate 41% of osteosarcoma cells without adversely affecting normal human osteoblasts. Moreover, glass compositions containing up to 1.3 mol% Nb2O5 significantly improved their ability to stimulate bone growth. The ability and kinetics of apatite deposition on SBF were investigated using 31P MAS NMR spectroscopy, which confirmed the formation of apatite within 3 hours for BGGN and 45S5 glasses, while glass compositions with higher niobium content (2.5 and 5.0 mol%) required at least 12 hours. In addition, BGGN glasses demonstrated their bio compatibility with BMMSC cells. They exhibited significantly increased proliferation of BMMSC cells after 4 days of treatment, while niobiumrich compositions stimulated osteogenic differentiation of BMMSCs after 21 days. Evaluation of the efficacy of BGGN glass for repair of critical-sized calvarial bone defects demonstrated good osteointegration in vivo models. The systemic biocompatibility study showed no evidence of toxicity. No fibrosis or cellular infiltrates occurred in the histologic microstructure of the liver and kidneys after 56 days of implantation. Taken together, these results demonstrate the potential for synergistic bone regeneration and targeted cancer therapy to open new avenues for the treatment of bone cancer.