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.

抽象的 骨折是最主要的肌肉骨骼损伤，每年影响超过 940 万美国人。大约 约 10% 的骨折因延迟愈合或不愈合而变得复杂，从而导致慢性疼痛、活动能力受损和 生活质量差。病理生理学和习惯性危险因素，包括骨折部位不稳定、并发 疾病（例如糖尿病）、长期接触某些药物（例如糖皮质激素或 GC）以及 烟草/酒精的使用也是主要原因，这可能会干扰骨折愈合的生物学特性 并导致愈合延迟或不愈合。 GC 广泛用于治疗住院的新冠肺炎患者。给定 当前大流行的规模以及美国人口中显着的新冠病毒感染率，一篇帖子 预计骨折风险会普遍激增，骨折愈合延迟也会出现这种情况。目前，骨科 手术和自体骨移植仍然是骨折延迟愈合临床治疗的金标准。 FDA 批准的非侵入性治疗干预措施很少用于治疗 GC 引起的延迟性 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 N-(2- 基于羟丙基）甲基丙烯酰胺（HPMA）的水溶性热响应性聚合物前药（P-TAN） 丹参酮 IIA（TAN，一种有效的骨合成代谢剂）。 P-TAN的水溶液在室温下可自由流动 温度并在 ≥ 27°C 时转变为水凝胶 (ProGel-TAN)，这提供了独特的机制 TAN 的持续本地交付。当在泼尼松诱导的骨折延迟愈合小鼠模型中进行测试时， 研究发现连续每月两次的 ProGel-TAN 治疗可将骨折愈合加速 5 周 没有观察到任何副作用。骨骼的生物力学特性也得到了完全恢复。尽管 每月两个月的 ProGel-TAN 治疗似乎非常有希望，目前的骨科实践倾向于单次治疗 出于实用原因以及减少感染，在骨折稳定手术时进行剂量治疗 风险。因此，我们假设通过进一步的结构和配方优化，我们将能够确定 优化的单剂量 ProGel-TAN 配方，在治疗 GC 诱导的癌症方面高效且安全 骨折延迟愈合。为了检验这一假设，我们在该项目中提出了三个具体目标： 1. 表征 ProGel-TAN 不同结构和配方参数的影响； 2. 识别单剂量 ProGel- TAN 配方可提供最佳的骨折愈合功效； 3.了解ProGel-TAN的独特之处 药理学和假定的作用机制。在成功完成拟议的研究后，我们 预计确定至少一种最佳 ProGel-TAN 配方，以满足对 单剂量治疗可加速 GC 引起的骨折延迟愈合约 5 周，并且 使小鼠受伤骨骼的生物力学特性正常化。然后将接受进一步的临床前研究 为临床转化做准备的大型动物模型研究。