Dual-Functional Dendritic Mesoporous Bioactive Glass Nanospheres for Calcium Influx-Mediated Specific Tumor Suppression and Controlled Drug Delivery in Vivo.

The development of nanomaterials for stable, controlled delivery of drugs and efficient suppression of tumor growth with desirable biosafety remains challenging in the nano-biomedical field. In this study, we prepared and optimized mesoporous bioactive glass (MBG) nanospheres to establish a functional drug delivery system and analyzed the effect of the dendritic mesoporous structure on drug loading and release. We then utilized an in vitro model to examine the biological effects of dendritic MBG nanospheres on normal and tumor cells and studied the molecular mechanism underlying specific tumor suppression by MBG nanospheres. Finally, we investigated the combinational effect of MBG nanospheres and a cancer therapeutic drug with an in vivo tumor xenograft model. Our results show that the dendritic MBG nanospheres have been successfully synthesized by optimizing calcium: silicon ratio. MBG nanospheres exhibit a dendritic mesoporous structure with a large specific surface area, demonstrate high drug loading efficiency, and release drugs in a controlled fashion to effectively prolong drug half-life. Ca2+ in nanospheres activates transient receptor potential channels and calcium-sensing receptor on tumor cells, mediates calcium influx, and directly regulates the calpain-1-Bcl-2-caspase-3 signaling pathway to specifically suppress tumor growth without affecting normal cells. In addition, dendritic MBG nanospheres synergize with cancer drugs to improve antitumor efficacy and reduce systemic toxicity. Dendritic MBG nanospheres with antitumor activity and controlled drug release have been successfully achieved and the underlying molecular mechanism was elucidated, paving the way for translational application.