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

小行星1450987 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吸收的不平衡引起的，影响约1400万美国人。2008年，美国的骨质疏松性骨折的医疗费用估计为220亿美元。大多数骨质疏松症疗法降低了骨吸收细胞的活性。开发靶向产生新骨基质的细胞的疗法（例如，因此，骨合成代谢药物）可以通过提供恢复骨健康的替代和/或协同机制来彻底改变骨质疏松症治疗。已经鉴定了几种骨合成代谢药物。然而，这些药物的全身给药具有低的骨蓄积（1%）和由于在骨以外的组织中蓄积而引起的严重副作用。因此，在开发向骨提供特异性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，这项工作旨在开发药物递送方法，以有效和特异性地将合成代谢药物靶向骨骼，以开发骨质疏松症的新治疗方法。这项研究的成功完成将大大推进骨质疏松症的治疗策略，所开发的方法将很容易适用于治疗其他骨骼疾病。此外，通过计划的实验确定的基本设计标准将为无数疾病的药物递送系统的设计提供见解，因为通用材料平台可以定制用于递送药物和组织靶向组的无限组合，从而产生巨大的变革和转化潜力。大多数骨质疏松症疗法是抗吸收的，仅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通过提供替代和/或协同机制来恢复骨健康，从而彻底改变骨质疏松症疗法。Wnt信号传导是一个关键的途径，集中精力开发骨合成代谢药物，因为它对骨形成和再生的重要性以及它在骨质疏松症发展中的下调。已经鉴定了几种Wnt激动剂。然而，包括Wnt激动剂在内的小分子药物的全身给药由于健康组织中Wnt信号传导的普遍存在而遭受低骨积累（1%）和严重的脱靶效应。在这项工作中，肽功能化，多价，和高度控制的聚（乙二醇）（PEG）为基础的聚合物将合成的目标骨吸收表面和可控释放Wnt激动剂。这些聚合物在体内骨重塑部位积聚，并已适于包括通过可释放的键连接以控制剂量和释放动力学的Wnt激动剂。将评估靶向肽、药物掺入和聚合物分子量对体外聚合物亲和力和体内骨化骨生物分布的影响。此外，还将研究通过聚合物治疗剂的时间控制的纵向药物释放在体外上调骨祖细胞Wnt信号传导和骨形成。最后，将描述靶向Wnt激动在神经退行性疾病小鼠模型中的再生功效。本文详述的方法是变革性的，因为它将为开发下一代靶向骨合成代谢药物递送系统的计划重点奠定基础。这种方法将为骨质疏松症提供替代和可能的上级治疗方法，与当前的抗骨吸收药物互补。通过该项目启动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，以提高对科学和工程的兴趣。此外，罗切斯特大学将举办一年一度的“扩大你的视野”外展活动，以培养当地中学生对科学、技术、工程和数学的兴趣。最后，罗切斯特大学对本科生指导的承诺也将继续下去，从而促进这些学生的智力发展和对技术的兴趣，并追求更高的学位。拟议的教育和推广工作的累积和长期影响将增加科学和工程领域的学生，特别是女孩和代表性不足的少数民族的入学率和保留率。这个职业奖由化学，生物工程，环境和运输系统司的生物技术和生物化学工程项目共同资助。

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.