The goal of this project is to develop a novel pharmacotherapeutic strategy for targeting the endochondral ossification process with spatiotemporal control. Accurate regulation of endochondral ossification is essential for musculoskeletal tissues. It govens normal skeletal formation and growth at childhood and is required for proper skeleton function and musculoskleletal repair in adults. A variety of orthopaedic pathologies are caused by or associated with impairment of systemic or local endochondral ossification. Fractures in the growth-plate (GP) could attenuate endochondral ossification progress, resulting in stunted bone growth whereas diaphyseal fractures in long bones provoke excessive bone growth, presumably due to regional activation of the GP function. In either case, the serious imbalance in bone growth inevitably leads to progressive deformity and significant physical problems. Heterotopic ossification (HO) is another pathological condition driven by ectopic induction of abnormal endochondral ossification. Therapeutic management of the long bone growth and genetic HO requires a long-term, site-specific treatment. Currently there is no drug that has shown adequate therapeutic effectiveness with local administration. During the pre-clinical and clinical studies on the selective nuclear retinoid receptors gamma agonist (RAR? agonist) for HO therapy, we have found that systemic administration of high doses of RAR? agonists causes early closure of GP and inhibits consequent bone growth while RAR? antagonists enhances cartilage growth and delay maturation of GP chondrocytes. These findings led us to hypothesize that RAR? agonists/antagonists may have a marked therapeutic potential for the treatment of conditions involving dysregulated endochondral ossification and bone growth. To this end, we designed nanoparticle (NP) formulations providing controlled release of a potent RAR? agonist. Locally applied drug-loaded NPs showed long retention in muscle and bone, releasing biologically activite RAR? agonist that strongly inhibited ectopic bone formation and logitudinal growth of the targeted bone. Guided by our preliminary results, the current project examines the central hypothesis that RAR ?-specific retinoids formulated in biodegradable nanoparticles for site-specific delivery to the musculoskeletal tissues will effectively control longitudinal growth of the targeted bone and inhibit HO. This hypothesis will be tested by pursuing two specific aims:
Aim 1, To develop and characterize the NP-based delivery system for RAR? agonists and antagonists;
and Aim 2, To determine pharmacological and therapeutic efficacy of these retionid-NPs. The outcomes should provide proof-of-principle for developing novel, nanocarrier-basede drug therapies for HO and for correcting bone growth imbalance that pose an unmet need for new, safer and more effective, treatment strategies.
This study proposes a multidisciplinary project conducted by researchers who have expertise on skeletal biology/pathology and material engineering. The long-term goals of the project are to establish the bioactive drug delivery system targeting a desired site of skeletal tissues and to prevent and cure musculoskeletal disorders. The specific goal of this proposal is to develop a local pharmacological tool that controls imbalance in bone growth and ectopic bone formation in soft tissues. Both conditions impair quality of life and may cause serious morbidity. At present, there is no effective drug-based therapy for those conditions. By encapsulating a group of Vitamin A delivatives, a potent regulator of cartilage formation and differentiation, in nano particles, we will generate safe and long-acting drugs that works locally at administered site. We anticipate that success in local and long-term delivery of test drugs enable us to develop a paradigm shift for orthopedic therapy.
