Localized nanoparticle-mediated delivery of miR-29b normalises the dysregulation of bone homeostasis caused by osteosarcoma whilst simultaneously inhibiting tumour growth.

Abstract

Patients diagnosed with osteosarcoma undergo extensive surgical intervention and chemotherapy resulting in dismal prognosis and compromised quality of life owing to poor bone regeneration, which is further compromised with chemotherapy delivery. This study aims to investigate if localised delivery of miR-29b--which has been shown to promote bone formation by inducing osteoblast differentiation and also to suppress prostate and glioblastoma tumour growth--would suppress osteosarcoma tumours whilst simultaneously normalising the dysregulation of bone homeostasis caused by osteosarcoma. Thus, we studied the therapeutic potential of miR-29b to promote bone remodelling in an orthotopic model of osteosarcoma (rather than in bone defect models using healthy mice), and in the context of chemotherapy, that is clinically relevant. We developed a formulation of miR-29b:nanoparticles that were delivered via a novel hyaluronic-based hydrogel to enable local and sustained release of the therapy, and to study the potential of attenuating tumour growth whilst normalising bone homeostasis. We found that when miR-29b was delivered along with systemic chemotherapy, compared to chemotherapy alone, our therapy provided a significant decrease in tumour burden, increase in mouse survival, and a significant decrease in osteolysis thereby normalising the dysregulation of bone lysis activity caused by the tumour.