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

1450987Benoit， Danielle该职业奖的目标是开发治疗骨质疏松症的靶向药物输送系统。骨质疏松症是由骨生成和骨吸收不平衡引起的，影响了大约1400万美国人。2008年，美国骨质疏松性骨折的医疗费用估计为220亿美元。大多数骨质疏松症治疗都降低了吸收骨骼的细胞的活性。因此，针对产生新骨基质的细胞的治疗方法（例如骨合成代谢药物）的开发可能会通过提供替代和/或协同机制来恢复骨骼健康，从而彻底改变骨质疏松症的治疗方法。已经确定了几种骨合成代谢药物。然而，这些药物的全身管理遭受低骨蓄积（1%）和严重的副作用，由于蓄积在骨骼以外的组织。因此，在开发针对骨骼提供特定治疗的药物递送方法方面存在关键的技术差距。为了克服这一挑战，本工作寻求开发药物递送方法，以有效和特异性地靶向骨合成代谢药物，以开发新的治疗骨质疏松症的方法。本研究的成功完成将大大促进骨质疏松症的治疗策略，并且所开发的方法将很容易适用于治疗其他骨骼疾病。此外，通过计划实验确定的基本设计标准将为无数疾病的药物输送系统设计提供见解，因为通用材料平台可以量身定制，以输送无限的药物和组织靶向组组合，从而产生巨大的变革和转化潜力。大多数骨质疏松症治疗是抗骨吸收的，仅作用于抑制过度活跃的破骨细胞。因此，骨选择性骨合成代谢疗法的发展可能会通过提供替代和/或协同机制来恢复骨骼健康，从而彻底改变骨质疏松症的治疗方法。由于Wnt信号在骨形成和再生中具有重要作用，并且在骨质疏松症的发生中下调，因此Wnt信号是开发骨合成代谢药物的关键途径。已经确定了几种Wnt激动剂。然而，由于Wnt信号在健康组织中普遍存在，包括Wnt激动剂在内的小分子药物的全身管理存在低骨蓄积（1%）和严重的脱靶效应。在这项工作中，多肽功能化、多价和高度可控的聚乙二醇（PEG）基聚合物将被合成，其靶向骨吸收表面并可控地释放Wnt激动剂。这些聚合物在体内骨重塑部位积聚，并已被用于包括Wnt激动剂，通过可释放的连接来控制剂量和释放动力学。将评估靶向肽、药物掺入和聚合物分子量对聚合物体外亲和力和体内骨质疏松性骨生物分布的影响。此外，将研究通过暂时控制的聚合物治疗药物纵向释放，骨祖细胞Wnt信号的上调和体外骨形成。最后，我们将描述靶向Wnt激动剂在骨质疏松小鼠模型中的再生功效。本文详细介绍的方法具有变革性，因为它将为下一代靶向骨合成代谢药物输送系统的开发奠定基础。这种方法将为骨质疏松症提供替代的，可能是更好的治疗方法，是对当前抗再吸收药物的补充。通过该项目发起的教育和推广工作将鼓励内城小学的科学参与。将为当地学校开发便携式动手示范模块，以提高学生对科学和工程的兴趣。此外，一年一度的“拓展你的视野”外展活动将在罗切斯特大学建立，以培养当地中学生对科学、技术、工程和数学的兴趣。最后，罗彻斯特大学对本科生的指导承诺也将继续，引导这些学生的智力发展和对技术的兴趣，并追求更高的学位。拟议的教育和外延努力的累积和长期影响将是增加科学和工程领域学生的入学人数和留校人数，特别是女孩和代表性不足的少数民族。该职业奖由化学、生物工程、环境和运输系统部门的生物技术和生物化学工程项目颁发，由材料研究部的生物材料项目共同资助。

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.