Bone-targeted polymer therapeutics for non-union fracture healing

每年有超过1500万美国人遭受骨折，其中5%导致骨不连。标准 骨不连的治疗是翻修手术：清创，然后自体移植和/或额外固定。 然而，翻修手术具有任何手术固有的风险，并且由于以下原因，高达60%的病例失败 潜在合并症。因此，治疗骨不连的新疗法是至关重要的，应予以重视。 通过无创输送或增加翻修手术成功率进行手术。间充质干细胞（MSC） 缺陷导致愈合不良。尽管有几种候选药物有望增加MSC 功能不愈合愈合，由于不良的骨折生物分布的副作用阻碍了发展。 因此，在向骨折部位输送强效再生药物方面存在关键的技术差距， 将生物分布限制在非靶组织，以提高安全性和临床可转化性。解决这些 为了克服这些障碍，我们开发了一种GSK-3 β的靶向纳米粒（NP）递送系统 抑制剂AR 28上调再生Wnt/β-连环蛋白途径。通过结合以下物质实现靶向 一种特异性结合抗酒石酸酸性磷酸酶（TRAP5b）的肽， 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聚集。骨折局部β-catenin激活 与未处理的、游离药物的、非靶向的NP和乱序肽NP对照相比大大增加。 在用TBP-NPAR 28治疗的骨折中观察到加速的骨痂形成，而对照组骨痂形成更快。 软骨骨痂骨化。最后，经治疗骨折的最大失效扭矩约为3 - 4倍 治疗4周后，与对照组相比，虽然有望加快传统骨折的愈合， 再生没有干预，这项技术的疗效必须在更严格的临床测试， 相关的临床前模型。我们假设TBP-NPAR 28将使药物输送到骨折不愈合， 老年和成年小鼠。为了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：评估TBP-NPAR 28预防成人和老年人骨不连的治疗效果 鼠模型。 目的2：评估TBP-NPAR 28在成人和老年完全确定的骨不连中的治疗效果 小鼠 这些目标的成功实现将大大提高我们针对药物的能力，以预防或 成人和老年骨折不愈合的愈合。

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.