CAREER: Polymer therapeutics for bone regeneration: next-generation osteoporosis treatments

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1450987Benoit, Danielle The goal of this CAREER Award is to develop targeted drug delivery systems to treat osteoporosis. Osteoporosis results from imbalances in bone production and resorption and affects ~14 million Americans. The US medical cost of osteoporotic fractures was estimated at $22 billion in 2008. The majority of osteoporosis therapies reduce the activity of cells that resorb bone. Development of therapies targeted towards cells that produce new bone matrix (e.g., bone anabolic drugs), therefore, may revolutionize osteoporosis therapies by offering an alternative and/or synergistic mechanism to restore bone health. Several bone anabolic drugs have been identified. However, systemic administration of these drugs suffers from low bone accumulation (1%) and serious side-effects due to accumulation in tissues other than bone. Thus, a critical technological gap exists in developing drug delivery approaches that provide specific treatment to bone. To overcome this challenge, this work seeks to develop drug delivery approaches to efficiently and specifically target anabolic drugs to bone to develop novel treatments for osteoporosis. Successful completion of this research will significantly advance therapeutic strategies for osteoporosis and the approaches developed will be readily adaptable to treat other bone diseases. Additionally, the fundamental design criteria determined via planned experiments will provide insights into the design of drug delivery systems for a myriad of diseases, as the general material platform can be tailored for delivery of unlimited combinations of drugs and tissue targeting groups, resulting in great transformative and translational potential.The majority of osteoporosis therapies are anti-resorptive, acting only to inhibit overactive osteoclasts. Development of bone-selective osteoanabolic therapies, therefore, may revolutionize osteoporosis therapies by offering an alternative and/or synergistic mechanism to restore bone health. Wnt signaling is a critical pathway on which to focus efforts to develop osteoanabolic agents due to its recognized importance for bone formation and regeneration and its downregulation in the development of osteoporosis. Several Wnt agonists have been identified. However, systemic administration of small molecule drugs including Wnt agonists suffer from low bone accumulation (1%) and serious off-target effects due to the prevalence of Wnt signaling in healthy tissues. In this work, peptide-functionalized, multivalent, and highly controlled poly(ethylene glycol)(PEG)-based polymers will be synthesized that target bone resorption surfaces and controllably release Wnt agonists. These polymers accumulate at sites of bone remodeling in vivo and have been adapted to include Wnt agonists tethered through releasable linkages to control dose and release kinetics. The impact of targeting peptide, drug incorporation, and polymer molecular weight on polymer affinity in vitro and osteoporotic bone biodistribution in vivo will be assessed. Additionally, the upregulation of osteoprogenitor Wnt signaling and bone formation in vitro through temporally controlled, longitudinal drug release from polymer therapeutics will be investigated. Finally, the regenerative efficacy of targeted Wnt agonism in osteoporotic murine models will be delineated. The approach detailed herein is transformative as it will lay the foundation for a programmatic focus in development of next-generation, targeted bone anabolic drug delivery systems. This approach will offer alternative and possibly superior therapeutics for osteoporosis that are complementary to the current cohort of anti-resorptive drugs.Educational and outreach efforts initiated through this project will encourage scientific engagement at inner city elementary schools. Portable, hands-on demonstration modules will be developed for local schools to increase interest in science and engineering. Additionally, an annual "Expanding Your Horizons" outreach event will be established at the University of Rochester to foster science, technology, engineering, and math interests in local middle school aged girls. Finally, the commitment to undergraduate mentoring at the University of Rochester will also be continued, leading to the intellectual development and interest in technology and pursuance of advanced degrees of these students. The cumulative and long-term impact of the proposed educational and outreach efforts will be increased enrollment and retention of students in science and engineering fields, particularly girls and underrepresented minorities.This CAREER Award by the Biotechnology and Biochemical Engineering Program in the Chemical, Bioengineering, Environmental, and Transport Systems Division is co-funded by the Biomaterials Program of the Division of Materials Research.