Effective local delivery of bone anabolic agent to accelerate the healing of delayed fracture union

有效局部输送骨合成代谢剂加速骨折延迟愈合

• 批准号: 10565241
• 负责人: Dong Wang
• 金额: $ 45.3万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-20 至 2027-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10565241
• 关键词: Acceleration; Address; Affect; Aftercare; Aging; Alcohol consumption; American; Anabolic Agents; Animal Model; Anticoagulants; Antiinflammatory Effect; Autoimmune Diseases; Autologous; Biodistribution; Biology; Biomechanics; Blood Vessels; Blood flow; Bone Injury; Bone Transplantation; Bone callus; COVID-19 patient; Cells; Characteristics; Chronic; Clinical; Clinical Management; Contrast Media; Development; Diabetes Mellitus; Disease; Dose; Drug Kinetics; Estrogen deficiency; Euthanasia; Event; Exhibits; Exposure to; FDA approved; Femoral Fractures; Femur; Flow Cytometry; Formulation; Fracture; Glucocorticoids; Goals; Hospitalization; Hydrogels; Immunofluorescence Immunologic; Impaired healing; Impairment; In Vitro; Inflammatory; Investments; Label; Lasers; Microfils; Molecular; Molecular Weight; Monitor; Mus; Operative Surgical Procedures; Orthopedic Surgery; Orthopedics; Osteogenesis; Osteoporosis; Pathologic; Perfusion; Pharmaceutical Preparations; Pharmacology; Pharmacology Study; Phase Transition; Polymers; Population; Postmenopause; Prednisone; Preparation; Procedures; Process; Prodrugs; Property; Quality of life; Regimen; Research; Resolution; Risk Factors; Safety; Salvia miltiorrhiza; Sampling; Site; Skeleton; Temperature; Testing; Therapeutic Agents; Therapeutic Intervention; Time; Tissues; Tobacco; Tobacco use; Transition Temperature; Treatment Efficacy; Viscosity; Water; Weight; X-Ray Medical Imaging; angiogenesis; aqueous; bone; bone fracture repair; bone quality; candidate selection; chronic pain; clinical efficacy; clinical translation; coronavirus disease; current pandemic; density; design; drug release kinetics; effective therapy; fracture risk; functional disability; healing; improved; in vivo; in vivo optical imaging; infection rate; infection risk; insight; lipophilicity; liquid chromatography mass spectrometry; methacrylamide; microCT; mouse model; musculoskeletal injury; novel; osteogenic; post-pandemic; preclinical study; side effect; standard care; water solubility

ABSTRACT Fracture is the leading musculoskeletal injury affecting over 9.4 million Americans annually. Approximately ~10% of fractures are complicated by delayed healing or non-union, resulting chronic pain, impaired mobility and poor quality of life. Pathophysiological and habitual risk factors, including fracture site instability, concurrent diseases (e.g., diabetes), chronic exposure to certain medications (e.g., glucocorticoids or GCs) and tobacco/alcohol use are also major contributing causes, which may interfere with the fracture healing biology and lead to delayed healing or non-union. GCs are widely used in treating hospitalized COVID patients. Given the scale of the current pandemic and the significant COVID infection rate among the US population, a post pandemic surge of fracture risk and delayed fracture healing cases may be anticipated. Currently, orthopaedic surgery and autologous bone grafts are still the gold standard in clinical management of delayed fracture healing. There are few FDA approved non-invasive therapeutic interventions for the treatment of GC-induced delayed fracture healing. To address this significant unmet clinical need, we have developed a N-(2- hydroxypropyl)methacrylamide (HPMA)-based water-soluble thermoresponsive polymeric prodrug (P-TAN) of Tanshinone IIA (TAN, a potent bone anabolic agent). The aqueous solution of P-TAN is free-flowing at room temperature and transitions into a hydrogel (ProGel-TAN) at ≥ 27°C, which provide a unique mechanism for sustained local delivery of TAN. When tested in a prednisone-induced delayed fracture healing mouse model, two consecutive monthly ProGel-TAN treatments were found to accelerate the fracture healing by 5 weeks without any side effects observed. The biomechanical properties of the bone were also fully restored. While two monthly ProGel-TAN treatment seems to be very promising, the current orthopaedic practice favors a single dose treatment at the time of the fracture stabilization procedure for pragmatic reasons as well as less infection risk. Therefore, we hypothesize that with further structural and formulation optimization, we will be able to identify an optimized single dose ProGel-TAN formulation that is highly effective and safe in treating the GC-induced delayed fracture union. To test this hypothesis, we propose three Specific Aims in this project: 1. To characterize the impact of different structural and formulation parameters of ProGel-TAN; 2. To identify single dose ProGel- TAN formulations that provide optimal fracture healing efficacy; 3. To understand ProGel-TAN’s unique pharmacology and putative mechanisms of action. At the successful completion of the proposed research, we anticipate the identification of at least one optimal ProGel-TAN formulation that would satisfy the demand for a single dose treatment to accelerate the healing of the GC-induced delayed fracture union by ~ 5 weeks and normalize biomechanical properties of the injured bone in mice. It will then be subjected to further pre-clinical studies on large animal models in preparation for clinical translation.

摘要 骨折是主要的肌肉骨骼损伤，每年影响超过940万美国人。约 约10%的骨折并发延迟愈合或骨不连，导致慢性疼痛、活动能力受损， 生活质量差。病理生理和习惯性风险因素，包括骨折部位不稳定，并发症 疾病（例如，糖尿病），长期暴露于某些药物（例如，糖皮质激素或GC）和 吸烟/饮酒也是主要的原因，这可能会干扰骨折愈合生物学 并导致延迟愈合或不愈合。GC广泛用于治疗住院的COVID患者。给定 当前疫情的规模和美国人口中的COVID感染率， 骨折风险和延迟骨折愈合病例的流行性激增是可以预期的。目前，骨科 手术和自体骨移植仍然是临床治疗骨折延迟愈合的金标准。 FDA批准的非侵入性治疗干预用于治疗GC诱导的迟发性 骨折愈合为了解决这一重大的未满足的临床需求，我们开发了一种N-（2- 羟丙基）甲基丙烯酰胺（HPMA）基水溶性温敏性聚合物前药（P-TAN） 丹参酮Ⅱ A（TAN，a potent bone anabolic agent）. P-TAN的水溶液在室温下是自由流动的。 在≥ 27°C温度下转变为水凝胶（ProGel-TAN），这为生物降解提供了独特的机制。 持续的TAN局部递送。当在泼尼松诱导的骨折延迟愈合小鼠模型中进行测试时， 连续两个月的ProGel-TAN治疗被发现可以加速骨折愈合5周 没有观察到任何副作用。骨的生物力学性能也得到了完全恢复。而 两个月的ProGel-TAN治疗似乎是非常有希望的，目前的骨科实践倾向于单一的 在骨折稳定手术时进行剂量治疗，以减少感染 风险因此，我们假设，通过进一步的结构和配方优化，我们将能够识别 一种优化的单剂量ProGel-TAN制剂，在治疗GC诱导的 骨折延迟愈合。为了验证这一假设，我们提出了三个具体目标：1。表征 ProGel-TAN的不同结构和制剂参数的影响; 2.为了确定单剂量ProGel- 提供最佳骨折愈合功效的TAN制剂; 3.了解ProGel-TAN独特的 药理学和假定的作用机制。在成功完成拟议的研究后，我们 预期鉴定至少一种最佳的ProGel-TAN制剂，其将满足对 单次给药治疗可加速GC诱导的延迟骨折愈合约5周， 使小鼠受损骨骼的生物力学特性正常化。然后将其进行进一步的临床前 为临床转化做准备的大型动物模型研究。