Controlled Intra-Tumoral Delivery of Doxorubicin from a Ceramic Biomaterial Combined with Systemic Chemotherapy for Treatment of an Aggressive Osteosarcoma in Mice

Abstract

Background/Aim: Osteosarcoma (OS) treatment consists of chemotherapy with methotrexate, adriamycin (doxorubicin) and platinol (MAP) combined with intercalated surgery, resulting in a 5-year survival rate of 50–60%. We recently demonstrated that local delivery of doxorubicin via a microparticulate hydroxyapatite-based biomaterial (DASH) could efficiently impede tumor growth in subcutaneous OS; however, its effect in an orthotopic intraosseous OS remains unknown, particularly in conjunction with systemic MAP treatment. In this study, we performed two separate mouse model studies with the aim of (1) evaluating the effect of DASH in an orthotopic osteosarcoma model and (2) evaluating the efficacy and tolerability of DASH in conjunction with systemically administered MAP in a subcutaneous osteosarcoma model. Methods: In the first study, 56 mice were inoculated with human OS cells (i.e., h143B cells) in the proximal tibia. After 10 days, the mice were divided into seven treatment groups, of which group G2 (systemic DOX) was compared with groups G5–G7, which were treated with increasing doses of DOX delivered via DASH. The tumor-impeding response was evaluated via micro-CT (day 14), PET-CT (day 21) and tumor measurements (post-mortem). In the second study, 45 mice were inoculated subcutaneously with 143B cells and, 10 days later, groups G2–G5 were treated locally with increasing DASH doses, followed by two cycles of systemic MAP for all groups. On day 31, the animals underwent PET-CT examination followed by euthanasia and tumor measurements. Results: In both experiments, DASH treatment resulted in significantly lower tumor activity, tumor volume and weight. Micro-CT examination in the orthotopic model demonstrated that DASH treatment protected the bone from osteolysis. The subcutaneous study revealed that the mice were able to tolerate DASH, even in conjunction with systemically administered MAP. Conclusions: Intratumoral administration of DASH impeded OS growth in both animal models and protected bone against tumor-induced osteolysis. Furthermore, DASH was well-tolerated when administered in conjunction with systemic MAP therapy, indicating its potential therapeutic neo-adjuvant value in poor responders.