Bone-targeted polymer therapeutics for non-union fracture healing

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。间充质干细胞 缺陷是愈合不良的基础。尽管几种候选药物承诺增强MSC 对于骨不连愈合的功能，由于骨折生物分布不佳而产生的副作用阻碍了发展。 因此，在将有效的再生药物输送到骨折部位方面存在关键的技术差距，而 将生物分布限制在靶外组织，以提高安全性和临床可译性。要解决这些问题 障碍，我们已经为葛兰素史克-3β开发了一种基于骨折靶向纳米颗粒(NP)的递送系统 抑制剂AR28上调再生的Wnt/β-连环蛋白途径。目标定位是通过合并 一种能与抗酒石酸酸性磷酸酶(TRAP5b)(一种基质结合蛋白)特异结合的多肽 在愈合过程中和骨不连时由破骨细胞沉积。TRAP5b结合肽(TBP)靶向NP 在常规股骨骨折处表现出优先堆积。β-连环蛋白在骨折局部的激活 与未经治疗的、游离药物、非靶向NP和杂乱肽NP对照相比，大大增加。 在TBP-NPAR28治疗的骨折中观察到比对照组更快的骨痂形成 软骨骨痂骨化。最后，经治疗的骨折的最大失效扭矩是原来的3-4倍 治疗4周后与对照组比较，差异有统计学意义。虽然承诺加快传统骨折的愈合，但这将 在没有干预的情况下再生，这项技术的有效性必须在更严格的临床和 相关的临床前模型。我们假设TBP-NPAR28将使药物传递能够治疗骨折不愈合。 老龄和成年小鼠。基于使用这种方法治疗骨折不愈合的长期目标，我们建议 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。

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.