Development of controlled release systems forfracture-targeted therapeutic delivery

Fracture healing is a major clinical challenge, with a 10-20% impaired healing rate, resulting in significantly prolonged hospitalization, decreased quality of life, and substantial healthcare costs. Currently, myriad therapeutics that target various mechanisms and signaling pathways have been developed to augment fracture healing. Apart from bone morphogenic protein (BMP) implants, there are currently no FDA approved fracture healing enhancement drugs on the market. A major challenge of the bench side to bedside translation is efficient drug delivery. This motivates the goal of this dissertation, which is to develop successful drug delivery systems that can overcome critical barriers to realize clinical translation. Drug delivery barriers to bone fracture enhancement therapies include short half-life in vivo, non-specific accumulation in healthy tissue, as well as associated side effects. The studies herein provide strategies for local and systemic drug delivery. Specifically, the local delivery system in this thesis consists of polymer-based hydrogels loaded with siRNA/nanoparticle (NP) complexes. The local drug delivery system takes advantages of the NP’s ability to protect siRNA and facilitate cell uptake, and the hydrogel’s ability to localize and sustain the encapsulated content at the fracture site. Results showed controlled release of siRNA/NPs complexes from hydrogels through hydrolytic degradation. Localization of NPs at fracture was associated with degradation rates of hydrogels such that hydrogels with the slowest degradation rates yielded longer localization at fracture. Hydrogels that delivered siNRA/NP for ~ 1 month were implanted in a murine fracture model, and in vivo gene silencing efficiency indicated potent and expedited healing. In the systemic drug delivery system, polymeric NPs with bone-targeting peptides conjugated onto the NP corona were used to realize bone targeting efficacy. Potent fracture-targeting efficiency was observed, and NPs accumulated at fractures for ~ 7 days. NPs loaded with a small molecule GSK-3β inhibitor and showed fracture site-specific β-catenin agonism, enhanced bone mechanical properties, and faster healing rates. Taken together, the two drug delivery strategies explored here establish solid platforms for design of next generation drug delivery systems to fracture.