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.

在每年超过1500万的美国人中，有5%的人会导致骨不连。标准 骨不连的处理是翻修手术：清创，然后是自体移植，和/或附加固定。 然而，翻修手术带有任何手术固有的风险，在高达60%的病例中失败是因为 潜在的合并症。因此，治疗骨不连的新疗法是至关重要的，应该被排除。 通过无创分娩进行手术或增加翻修手术的成功率。总体上是减少了 临界大小缺损区内间充质干细胞的数量和再生能力。骨髓间充质干细胞缺乏会减少软骨和 骨形成、软骨痂改建、矿化和关键成骨生长因子的表达 在老茧里。此外，长期的炎症也会导致与衰老相关的变化。 非工会发展。尽管几种候选药物承诺增强MSC的功能 骨折生物分布不良导致的骨不连愈合和副作用阻碍了骨折的发展。因此，一个 在将有效的、可再生的药物输送到骨折部位方面存在关键技术差距，同时限制了 生物分布到靶外组织，以提高安全性和临床可译性。为了解决这些障碍，我们 已经为葛兰素史克-3β抑制剂ar28开发了一种基于骨折靶向纳米颗粒(NP)的递送系统 上调再生的Wnt/β-连环蛋白途径。靶向是通过掺入一种多肽来实现的 与抗酒石酸酸性磷酸酶(TRAP5b)特异性结合，TRAP5b是一种与基质结合的蛋白质，由 在愈合和骨不连过程中的破骨细胞。TRAP5b结合肽(TBP)靶向NP展示 在常规股骨骨折处优先堆积。β-连环蛋白在骨折局部的激活作用显著 与未经治疗的、游离药物、非靶向NP和杂乱的多肽NP对照相比增加。已加快 在TBP-NPAR28治疗的骨折组与骨痂更快的对照组相比，观察到了骨痂的形成 骨化。最后，接受治疗的骨折的最大失效扭矩是对照组的3-4倍。 治疗后几周。然而，该技术在更临床相关的情况下的潜力(例如， 成人和老年模型中急性和已建立的骨折不愈合)对进一步发展、设置 提高这个高风险/高回报的提议。假设TBP-NPAR28将使药物输送到 为了促进老年和成年小鼠骨折不愈合的愈合，提出了以下目标： 目的1：评价TBP-NPAR28预防成人和老年人骨不连的疗效 小鼠模型。 目的2：评价TBP-NPAR28治疗成人和老年人完全骨不连的疗效 老鼠。 成功完成这些目标将大大提高我们针对药物进行预防或使 成人和老年骨不连骨折的愈合。