Bone-targeted polymer therapeutics for nonunion fracture healing

用于骨不连骨折愈合的骨靶向聚合物治疗

• 批准号: 10371267
• 负责人: Danielle S. Benoit
• 金额: --
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-15 至 2022-08-20
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10371267
• 关键词: Acute; Address; Adult; Aftercare; Age; Aging; Agonist; American; Animal Model; Atrophic; Autologous Transplantation; Binding; Binding Proteins; Biodistribution; Biological; Biomechanics; Bone callus; Cartilage; Clinical; Clinical Management; Critical Pathways; Data; Debridement; Defect; Deposition; Development; Drug Delivery Systems; Drug Targeting; Evaluation; Exhibits; Failure; Femoral Fractures; Fracture; Funding; Goals; Growth Factor; Histology; Human; Impairment; Inflammation; Injury; Intervention; Minerals; Modeling; Mus; Operative Surgical Procedures; Osteoclasts; Osteogenesis; Outcome; Outcome Measure; Pathway interactions; Peptides; Pharmaceutical Preparations; Pharmacology; Physiologic Ossification; Placebos; Polymers; Prevention; Public Health; Regenerative capacity; Research; Risk; Rodent; Safety; Signal Transduction; Site; System; Technology; Testing; Therapeutic; Therapeutic Effect; Tissues; Torque; Work; aged; animal imaging; base; beta catenin; biomaterial compatibility; biomechanical test; bone; bone fracture repair; bone healing; clinically relevant; clinically translatable; comorbidity; drug candidate; glycogen synthase kinase 3 beta inhibitor; healing; high reward; high risk; human old age (65+); improved; innovation; mineralization; minimally invasive; mouse model; nanoparticle; nanoparticle delivery; nanoparticle drug; novel therapeutics; osteogenic; prevent; prophylactic; radiological imaging; regenerative; regenerative approach; sample fixation; side effect; success; tartrate-resistant acid phosphatase

Of the more than 15 million Americans suffer from fractures each year, 5% result in nonunions. Standard nonunion management is revision surgery: debridement, followed by autograft, and/or additional fixation. However, revision surgery carries risks inherent to any surgery and fails in up to 60% of cases due to underlying comorbidities. Therefore, novel therapeutics for treating nonunions are critical and should obviate surgery through noninvasive delivery or increase revision surgery success. There is a reduction in overall number and regenerative capacity of MSCs within a critical sized defect. Deficient MSCs reduces cartilage and bone formation, soft callus remodeling, mineralization, and expression of critical osteogenic growth factors within the callus. Additionally, prolonged inflammation contributes to aging-related changes that underlie nonunion development. Despite the promise of several drug candidates for augmenting MSC function for nonunion healing, side effects due to poor fracture biodistribution have hampered development. Thus, a critical technological gap exists in delivery of potent, regenerative drugs to fracture sites while limiting biodistribution to off-target tissues to improve safety and clinical translatability. To address these hurdles, we have developed a fracture-targeted nanoparticle (NP)-based delivery system for the GSK-3β inhibitor AR28 to upregulate the regenerative Wnt/β-catenin pathway. Targeting is achieved by incorporation of a peptide that binds specifically to tartrate resistant acid phosphatase (TRAP5b), a matrix-bound protein deposited by osteoclasts throughout healing and at nonunions. TRAP5b-binding peptide (TBP) targeted NP exhibit preferential accumulation at conventional femur fractures. Fracture localized activation of β-catenin is greatly increased compared with untreated, free drug, untargeted NP, and scrambled peptide NP controls. Expedited callus formation was observed in fractures treated with TBP-NPAR28 versus controls with more rapid callus ossification. Finally, the maximum torque to failure of treated fractures was ~3-4-fold greater than controls 4 weeks after treatments. However, the potential of this technology within more clinically relevant situations (e.g., acute and established fracture nonunions in adult and aged models) is critical for further development, setting up this high-risk/high-reward proposal. With the hypothesis that TBP-NPAR28 will enable drug delivery to promote healing in fracture nonunions in aged and adult mice, the following aims are proposed: Aim 1: Assess the therapeutic effect of a TBP-NPAR28 for the prevention of nonunion in adult and aged murine models. Aim 2: Assess the therapeutic effect of TBP-NPAR28 in fully established nonunions in adult and aged mice. Successful completion of these Aims will significantly advance our ability to target drugs to prevent or enable healing of adult and aged nonunion fractures.

每年有超过 1500 万美国人遭受骨折，其中 5% 导致骨不连。标准 骨不连的处理是翻修手术：清创，然后进行自体移植和/或额外的固定。 然而，修复手术具有任何手术固有的风险，并且由于以下原因导致高达 60% 的病例失败： 潜在的合并症。因此，治疗不愈合的新疗法至关重要并且应该避免 通过无创分娩进行手术或增加翻修手术的成功率。整体上有减少 临界尺寸缺损内 MSC 的数量和再生能力。缺乏的 MSC 会减少软骨并 骨形成、软愈伤组织重塑、矿化和关键成骨生长因子的表达 愈伤组织内。此外，长期炎症会导致与衰老相关的变化 不工会的发展。尽管有几种候选药物有望增强间充质干细胞的功能 骨不连愈合、骨折生物分布不良导致的副作用阻碍了发育。因此，一个 在向骨折部位输送有效的再生药物方面存在关键的技术差距，同时限制了 生物分布到非目标组织以提高安全性和临床可转化性。为了解决这些障碍，我们 开发了一种基于断裂靶向纳米粒子（NP）的 GSK-3β 抑制剂 AR28 递送系统 上调再生 Wnt/β-catenin 通路。通过掺入肽来实现靶向 特异性结合酒石酸抗性酸性磷酸酶 (TRAP5b)，这是一种由沉积物沉积的基质结合蛋白 破骨细胞在整个愈合过程中和骨不连时。 TRAP5b 结合肽 (TBP) 靶向 NP 表现 传统股骨骨折处优先聚集。 β-连环蛋白的骨折局部激活显着 与未经处理、游离药物、非靶向 NP 和乱序肽 NP 对照相比有所增加。加急 在用 TBP-NPAR28 治疗的骨折中观察到骨痂形成，而对照组的骨痂形成速度更快 僵化。最后，治疗骨折的最大失效扭矩比对照组大约 3-4 倍 4 治疗后几周。然而，该技术在更多临床相关情况下的潜力（例如， 成人和老年模型中的急性和已确定的骨折不愈合）对于进一步发展至关重要，设置 提出这个高风险/高回报的建议。假设 TBP-NPAR28 将使药物递送 促进老年和成年小鼠骨折不愈合的愈合，提出以下目标： 目标 1：评估 TBP-NPAR28 对预防成人和老年人骨不连的治疗效果 小鼠模型。 目标 2：评估 TBP-NPAR28 对成人和老年人完全不愈合的治疗效果 老鼠。 成功完成这些目标将显着提高我们靶向药物预防或实现的能力 成人和老年骨折不愈合的愈合。