Development of Smoothened Agonist Nonphospholipid Liposomal Nanoparticles for Bone Repair
Abstract
Fiscal Year 2017 Peer Reviewed Medical Research Program Topic Area: Nanomaterials for bone regeneration. Area of Encouragement: (1) Development of controlled release/extended release of growth factors for enhanced bone regeneration and (2) technologies addressing segmental/large bone defects in craniofacial regions. Non-healing bone injuries represent a source of morbidity for combat casualties and military veterans, exacting both a devastating individual toll on the lives affected as well as an enormous socioeconomic burden. For example, recent studies show that such injured military personnel utilize a large portion of hospital resources, and do so with enormous immediate and downstream costs. Among the US population at large, bone defect pathologies are estimated to cost nearly $60 billion on a yearly basis. Better and more efficacious bone repair treatment strategies would have a high impact on both individual and socioeconomic levels, among both military and civilian populations. The manipulation of Hedgehog (Hh) signaling is a promising alternative for improved bone regeneration. Our research group has shown that Hh signaling diverts mesenchymal stem cells (MSC) toward a bone-forming fate and away from competing cell fates. Moreover, the Hh activating small molecule SAG targets bone and vascular formation to induce bone healing. In a coordinate research effort, we have shown that nonphospholipid liposomes composed of Stearylamine and Oxysterol (SA/Oxy) have intrinsic bone inducing capabilities and are well designed to deliver the small molecule SAG to sites of bone injury. In aggregate, the present proposal seeks to develop a nanoparticle (NP) delivered small molecule for faster, safer, and more efficacious bone repair than currently available treatment strategies. Here, we will perform key preclinical safety and efficacy studies for clinical translation of a nanoparticle packaged Hh small molecule for use as a widely applicable bone graft substitute, to be accomplished in two specific aims. Specific Aims: Aim 1: Optimize SAG-loaded liposomal nanoparticles for mouse calvarial defect repair. Here, we will optimize the small molecule packaged nanoparticles for bone formation. Defined primary study endpoints will include those quantitative markers of bone and vascular formation most reflective of successful bone healing. Next, a head-to-head comparison to currently available therapies will be performed. Aim 2: Determine the safety of SAG-loaded liposomal nanoparticles for mouse calvarial defect repair. Here, key short- and long-term safety studies will be performed so as to confirm our preliminary findings of a high safety profile for the SAG-loaded NP product. Applicability and Impact: Orthopaedic trauma represents a significant portion of wartime-related trauma, with an estimated 70% of war wounds involving the musculoskeletal system. The present proposal seeks to improve our ability to speed bone regeneration and repair by employing a novel combination of small molecule stimulus with nanomaterial-based delivery. The combination product would be pre-formulated, allowing for ease of deployment in virtually any clinical situation in which bone regeneration is desired. In the short term, use of Hh small molecule agonists could shift the current paradigm for local bone healing away from protein-based stimulation of the bone morphogenetic protein (BMP) signaling pathway. In the long term, a SAG-loaded NP therapy could be used in any circumstance that bone grafting is required, directly addressing nearly $60 billion in costs per annum for bone defect pathologies, and benefiting both military and civilian populations.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810336
Entities
People
- Aaron W James
Organizations
- Johns Hopkins University
- United States Army