Hyaluronate-based Self-stabilized Nanoparticles for Reverting Immunosuppression and Immunochemotherapy in Osteosarcoma Treatment 

Abstract Background: Chemotherapy and immunotherapy are the mainly non-surgical treatment for osteosarcoma in clinic presently. However, serious side effects, short blood circulation time, and immunosuppressive tumor microenvironment have extremely limited their application. To generate an onsite combined chemotherapy and immunotherapy regimen, we designed a self-stabilized hyaluronic acid (HA) nanoparticle for the tumor-targeting delivery of doxorubicin (DOX), cisplatin (DDP), and resiquimod (R848) in osteosarcoma treatment, referred to as DDPNPDOX&R848. Methods: Here, we tested the physicochemical properties of and the ability of DDPNPDOX&R848 to induce immunogenic cell death (ICD) and revert immunosuppressive cells were characterized in vitro. The therapeutic efficacy of DDPNPDOX&R848 in vivo was evaluated in an orthotopic osteosarcoma mouse model. Furthermore, we also verified the immune memory evoking effect of DDPNPDOX&R848 in an osteosarcoma rechanllenge mouse model.Results: DDPNPDOX&R848 possesses a uniform size (similar to 190 nm) and ideal pH responsibility, and its ability to induce ICD and modulate immune cells was also proven. In vivo, regardless of the mouse model used (i.e., orthotopic osteosarcoma or rechanllenge xenografted osteosarcoma), DDPNPDOX&R848 showed significantly enhanced tumor inhibition and prolonged survival. Evoked tumoricidal immune memory responses were also demonstrated in the rechanllenged osteosarcoma mouse model.Conclusion: In summary, this intelligent codelivery platform might be a competitive candidate for osteosarcoma immunochemotherapy.