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Localized Nanoparticle-Mediated Delivery of miR-29b Normalizes the Dysregulation of Bone Homeostasis Caused by
Fiona E Freeman1,2,3,4,5,6,7, Pere Dosta3,4,8, Lianne C Shanley1,5,9
1Trinity Centre for Biomedical Engineering, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, D02 PN40, Ireland.
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 localized delivery of miR-29b-which is shown to promote bone formation by inducing osteoblast differentiation and also to suppress prostate and cervical tumor growth-can suppress osteosarcoma tumors whilst simultaneously normalizing the dysregulation of bone homeostasis caused by osteosarcoma. Thus, the therapeutic potential of microRNA (miR)-29b is studied to promote bone remodeling 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. A formulation of miR-29b:nanoparticles are developed that are delivered via a hyaluronic-based hydrogel to enable local and sustained release of the therapy and to study the potential of attenuating tumor growth whilst normalizing bone homeostasis. It is found that when miR-29b is delivered along with systemic chemotherapy, compared to chemotherapy alone, the therapy provided a significant decrease in tumor burden, an increase in mouse survival, and a significant decrease in osteolysis thereby normalizing the dysregulation of bone lysis activity caused by the tumor.
Insights
Localized delivery of microRNA (miR)-29b with chemotherapy significantly reduced osteosarcoma tumor burden and bone damage. This novel approach improved survival and normalized bone homeostasis in preclinical models.
Area of Science:
- Biomedical Engineering
- Oncology
- Regenerative Medicine
Background:
- Osteosarcoma treatment involves surgery and chemotherapy, often leading to poor bone regeneration and quality of life.
- Chemotherapy can further impair bone healing, complicating patient recovery and prognosis.
- Current treatments struggle to address both tumor suppression and bone homeostasis restoration.
Purpose of the Study:
- To investigate the therapeutic potential of localized microRNA (miR)-29b delivery for osteosarcoma.
- To assess if miR-29b can suppress osteosarcoma growth while normalizing bone homeostasis.
- To evaluate miR-29b efficacy in conjunction with systemic chemotherapy in a clinically relevant model.
Main Methods:
- Development of a miR-29b:nanoparticle formulation delivered via a hyaluronic-based hydrogel for sustained local release.
- Utilizing an orthotopic osteosarcoma mouse model to mimic clinical conditions.
- Comparing the effects of miR-29b combined with chemotherapy against chemotherapy alone.
Main Results:
- Combined miR-29b and chemotherapy significantly decreased tumor burden compared to chemotherapy alone.
- The therapy led to a significant increase in mouse survival rates.
- Osteolysis was significantly reduced, indicating normalization of bone lysis activity disrupted by the tumor.
Conclusions:
- Localized miR-29b delivery, when combined with chemotherapy, offers a promising therapeutic strategy for osteosarcoma.
- This approach effectively attenuates tumor growth and mitigates chemotherapy-induced bone damage.
- miR-29b holds potential for improving both cancer treatment outcomes and bone health in osteosarcoma patients.
