CeO2 Nanoparticles-Loaded pH-ResponsiveMicroparticles with Antitumoral Properties as Therapeutic Modulatorsfor Osteosarcoma

摘要

Osteosarcoma is an aggressive form of bone cancer mostly affecting young people. To date, the most effective strategy for the treatment of osteosarcoma is the surgical removal of the tumor with or without combinational chemotherapy. In this study, we present the development of a pH-sensitive drug-delivery system in the form of microparticles, with increased chemotherapeutic action against the osteosarcoma cell line SAOS-2, and with reduced toxicity against the heart myoblastic cell line H9C2. The delivery system is composed of calcium carbonate and collagen type I, and is loaded with cerium dioxide (CeO2) nanoparticles (<25 nm) and the anticancer drug doxorubicin. The fabricated microparticles were fully characterized morphologically and physicochemically, and their ability to induce or inhibit apoptosisecrosis was assessed using in vitro functional assays and flow cytometry. The results presented in this study show that the highest concentration (250 μg/mL) of the therapeutic microparticles (CaCO3-based therapeutic modulators (C-TherMods)), which corresponds to 6.4 μg/mL of encapsulated doxorubicin, can protect the H9C2 cells even after 120 h, since the percentage of viable cells at thistime point is 65%. On the contrary, when H9C2 cells are treated with0.5 μg/mL of free doxorubicin, 75% of the cells are dead onlyafter 24 h. When SAOS-2 cells are treated with the same concentrationof C-TherMods (250 μg/mL), the viability of SAOS-2 cells is80% after 24 h, while it reduces to 50% after 120 h. At pH 6.0, thesynergic effect of the pro-oxidant CeO2 nanoparticles andof the encapsulated doxorubicin leads to almost 100% of cell death,even at the lowest concentration of C-TherMods (50 μg/mL).