Bone-targeted polymer delivery of osteoanabolics for bone regeneration

Thesis (Ph. D.)--University of Rochester. Department of Biomedical Engineering, 2018.Bone is a dynamic organ with ~4% the total surface constitutively undergoing active remodeling. Under normal homeostatic conditions, bone resorption balances bone formation. Due to disease co-morbidities, including osteoporosis, obesity, and alcohol use that hinder normal bone regeneration, 10-20% of the >6 million annual fractures in the United States will not fully heal. To noninvasively stimulate bone regeneration, small-molecule osteoanabolic compounds such as Wnt/β-catenin signaling agonists have great potential. However, less than 1% of injected small-molecule doses reach bone, severely limiting pharmacodynamics and increasing the risk of deleterious effects due to off-target Wnt signaling. To address these limitations, a bone-targeting drug delivery system was developed using a peptide with high affinity to tartrate-resistant acid phosphatase (TRAP). TRAP is an enzyme specifically expressed by osteoclasts in remodeling bone, where druggable cells are localized. Polymer architectures were designed to favorably present targeting peptides and exploit multivalent binding. Five-fold greater bone biodistribution resulted for targeted polymers relative to untargeted controls. A hydrolytically degradable alkyne-functionalized drug linker was designed to incorporate therapeutic compounds into bone-targeting polymers via azide-based “click” chemistry to enable uniform, tunable drug release. Finally, a small-molecule Wnt signaling agonist was investigated for doses and dosing regimens that stimulate osteogenesis of mesenchymal stem cells. Continuous dosing sustained canonical Wnt/β-catenin activity and led to robust increases in collagen matrix deposition and mineralization, underscoring the need for controlled drug delivery. This work is clinically significant for the development of bone-targeting polymer therapeutics that reinitiate bone formation in patients suffering from osteoporosis, fractures, and osteolytic lesions. Due to site-specific delivery, targeted conjugates may reduce toxicity and off-target effects