Bone-targeted polymer therapeutics for non-union fracture healing

用于骨不连骨折愈合的骨靶向聚合物治疗

• 批准号: 10733942
• 负责人: Danielle S. Benoit
• 金额: $ 18.44万
• 依托单位: UNIVERSITY OF OREGON
• 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 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10733942
• 关键词: Bone; targeted; polymer; therapeutics; non

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. Mesenchymal stem cell (MSC) deficiencies underpin poor healing. 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 ossification of cartilage callus. Finally, the maximum torque to failure of treated fractures was ~3-4-fold greater than controls 4 weeks after treatments. While promising to expedite healing in conventional fractures that will regenerate without intervention, the efficacy of this technology must be tested in more clinically rigorous and relevant preclinical models. We hypothesize that TBP-NPAR28 will enable drug delivery to fracture nonunions in aged and adult mice. With a long-term goal of treating fracture nonunions using this approach, we propose the following aims: 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。 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： 因此，治疗骨不连的治疗小说至关重要，应该避免潜在的合并症。 通过无创递送进行手术或增加间充质干细胞（MSC）修复手术的成功率。 尽管有几种候选药物有望增强间充质干细胞，但缺陷仍然是治疗效果不佳的原因。 骨不连愈合的功能，由于骨折生物分布不良而产生的副作用阻碍了发育。 因此，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 限制生物分布到非目标组织以提高安全性和临床可转化性来解决这些问题。 克服障碍，我们为 GSK-3β 开发了一种基于断裂靶向纳米颗粒 (NP) 的递送系统 抑制剂 AR28 上调再生 Wnt/β-catenin 通路是通过掺入来实现的。 一种与酒石酸抗性酸性磷酸酶 (TRAP5b) 特异性结合的肽，TRAP5b 是一种基质结合蛋白 破骨细胞在愈合过程中和 TRAP5b 结合肽 (TBP) 靶向的 NP 处沉积。 β-连环蛋白在传统股骨骨折处优先聚集。 与未处理、游离药物、非靶向 NP 和乱序肽 NP 对照相比，大大增加。 在用 TBP-NPAR28 对照治疗的骨折中观察到骨痂形成加快，与更快速的治疗相比 最后，治疗后骨折的最大断裂扭矩增加了约 3-4 倍。 治疗后 4 周优于对照组，同时有望加速传统骨折的愈合。 在无需干预的情况下再生，这项技术的功效必须经过更严格的临床和更严格的测试。 我们研究了相关的临床前模型，认为 TBP-NPAR28 将能够实现药物递送以治疗骨折不愈合。 为了使用这种方法治疗骨折不愈合的长期目标，我们提出了 以下目标： 目标 1：评估 TBP-NPAR28 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。