Numbers Matter: The Role of Cell Dose in the Treatment of Osteosarcoma Using Mesenchymal Stromal Cells as Cellular Vehicles

A promising approach enhancing osteosarcoma (OS) prognosis involves the combination of various techniques, such as chemo- and photodynamic therapy, delivered through nanocarriers for synergistic cell death. Among the potential candidates for improving drug accumulation at the tumor site, mesenchymal stromal cells (MSCs) exhibit a significant advantage due to their tumor-homing ability and intracellular drug retention. This study evaluates the efficacy of chemo-releasing and photoactive bimodal nanoparticles, kPCe6 NPs, delivered via MSCs. In vitro analyses show that cells internalize and retain kPCe6 NPs in a dose-dependent manner and that kPCe6-loaded cells induce massive tumor cell death in a tridimensional tumor model. Results from an in vivo orthotopic OS murine model show negligible tumor cell death upon peritumoral administration of two doses containing 10(6) loaded cells. To gain insight into this observation, this work investigates the role of cell dose in treatment efficacy. The results indicate that achieving a tumor reduction higher than 90% requires a substantial number of loaded cells, approximately 35% of the entire tumor mass, highlighting the criticality of the cell dose for the success of this therapeutic approach and its potential impact on clinical translation in OS patients, particularly when the number of tumor cells is limited.