The combination of mesoporous silica nanoparticles (MSNs) with a second material to produce nanocarriers is a strategy to enhance their functionalities. Hydroxyapatite (HAP) is a judicious choice due to its high biocompatibility and osteoconductive and noninflammatory behavior. Herein, we explored the independent advantages of MSNs and HAP by incorporating HAP nanocrystals in the MSNs using different approaches. We demonstrated that by adjusting the synthesis conditions, we modulated, at the nanoscale level, how HAP was integrated into mesoporous silica, either as separated phases (MSN-HAP) or as combined phases in one structure (HAP@ MSN). The materials MSN-HAP and HAP@MSN were loaded with doxorubicin (DOX), as a drug model, and were compared with MSNs regarding their physicochemical characteristics, DOX release kinetics, cytotoxicities toward esophagus 2D and 3D (spheroids) cancer cells, and in vivo biochemical effects. The produced DOX-loaded nanocarriers showed tuned properties; e.g., not only did HAP retard the DOX release in comparison with pure MSNs, but also the way the HAP was integrated dictated the kinetics of DOX release. The cytotoxicity studies showed that the presence of HAP prolonged the DOX effect. The biochemical analysis of MSN-HAP-DOX and HAP@MSN-DOX indicated a transient alteration in the liver metabolism, whereas HAP@MSN-DOX had a modest effect on mouse fat metabolism. Therefore, benefiting from the bone-regeneration feature of HAP and the controlled drug release, we envision that MSN-HAP and HAP@MSN are promising materials for clinical translation as long-acting release formulations, especially for bone cancer treatment.
