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.

在每年有1500万美国人遭受骨折的痛苦中，有5％会导致不连接。标准 不工会管理是修订手术：调试，然后进行自体移植和/或其他固定。 但是，修订手术会带来任何手术固有的风险，并且由于 基础合并症。因此，新的治疗骨骼治疗至关重要，应消除 通过非侵入性分娩或增加修订手术成功的手术。总体上有所减少 关键大小缺陷中MSC的数量和再生能力。缺陷MSC可减少软骨和 骨形成，软愈伤组织重塑，矿化和临界成骨生长因子的表达 在愈伤组织中。此外，长时间的炎症有助于与衰老有关的变化 不工会发展。尽管有几名候选药物有望扩大MSC功能 骨不连愈合，由于骨折生物分布不良而引起的副作用阻碍了发展。那， 在限制的同时，将潜在的，再生药物传递到骨折部位的潜力，再生药物的关键技术差距存在 生物分布到脱靶时间，以提高安全性和临床转换性。为了解决这些障碍，我们 已经开发了针对骨折的纳米颗粒（NP）的GSK-3β抑制剂AR28的递送系统 上调再生Wnt/β-catenin途径。通过掺入肽来实现靶向 特异性地结合了抗tartrate抗性酸性磷酸酶（TRAP5B），这是一种沉积的基质结合的蛋白 整个愈合和未连接的破骨细胞。 TRAP5B结合肽（TBP）靶向NP展示 在常规股骨骨折上的优先积累。 β-catenin的断裂局部激活很棒 与未经治疗的免费药物，未靶向的NP和炒肽NP对照相比增加。加快 在用TBP-NPAR28处理的裂缝中观察到愈伤组织形成，而对照组则更快 骨化。最后，治疗裂缝失败的最大扭矩比对照组大约3-4倍4 治疗后几周。但是，这项技术在更临床相关的情况下的潜力（例如 成人和老年模型中的急性和已建立的骨折不连接）对于进一步发展至关重要 提高这个高风险/高回报的建议。假设TBP-NPAR28将使药物输送到 促进老年小鼠和成年小鼠骨折骨不连的愈合，提出了以下目的： AIM 1：评估TBP-NPAR28对预防成人和老年骨不连的治疗作用 鼠模型。 AIM 2：评估TBP-NPAR28在成人和老年的完全建立的骨骼中的治疗作用 老鼠。 成功完成这些目标将大大提高我们针对药物预防或启用药物的能力 成人和老年骨折的愈合。