Local Control of endochondral ossification by retinoid-loaded nano-particles

该项目的目标是开发一种新的针对软骨内的药物治疗策略。 具有时空控制的骨化过程。软骨内骨化的准确调节对于 肌肉骨骼组织。它在儿童时期影响正常的骨骼形成和生长，是正常发育所必需的 成人骨骼功能和肌肉骨骼修复。各种各样的骨科病理是由或引起的 与全身或局部软骨内骨化受损有关。生长板骨折(GP) 可延缓软骨内骨化进程，导致骨骼发育迟缓，而骨干 长骨骨折会刺激过度的骨生长，可能是由于GP功能的局部激活。 在任何一种情况下，严重的骨生长不平衡不可避免地导致进行性畸形和显著的 身体上的问题。异位骨化(HO)是由异位诱导引起的另一种病理状态 异常软骨内骨化。长骨生长和遗传性HO的治疗管理需要 一种长期的、针对特定部位的治疗。目前还没有一种药物显示出足够的治疗效果。 与当地政府合作。选择性核维甲酸受体的临床前和临床研究 伽马激动剂(RARγ激动剂)用于HO治疗，我们发现全身给予大剂量的 RARγ激动剂导致GP早期闭合并抑制随后的骨生长，而RARγ拮抗剂 促进软骨生长，延缓GP软骨细胞成熟。这些发现使我们假设 RARγ激动剂/拮抗剂可能具有显著的治疗潜力，用于治疗 软骨内骨化和骨生长失调。为此，我们设计了纳米颗粒(NP) 提供有效的RARγ激动剂的控制释放的配方。当地应用的载药NPs显示 在肌肉和骨骼中长期滞留，释放生物活性的RARγ激动剂，强烈抑制异位 靶骨的骨形成和纵向生长。在我们初步结果的指导下，目前的项目 检验了中心假设，即RARγ特异性维甲酸是在可生物降解的纳米颗粒中形成的 对于部位特定的递送到肌肉骨骼组织将有效地控制纵向生长 靶向骨骼和抑制HO。这一假设将通过追求两个具体目标来检验：目标1，开发 并表征了基于NP的RAR激动剂和拮抗剂的递送系统；以及目标2，确定 这些维甲酸纳米粒的药理和治疗效果。结果应提供原则证明 开发基于纳米载体的治疗HO的新型药物疗法，并纠正骨生长失衡， 对新的、更安全、更有效的治疗策略提出了尚未得到满足的需求。

The goal of this project is to develop a novel pharmacotherapeutic strategy for targeting the endochondral ossification process with spatiotemporal control. Accurate regulation of endochondral ossification is essential for musculoskeletal tissues. It govens normal skeletal formation and growth at childhood and is required for proper skeleton function and musculoskleletal repair in adults. A variety of orthopaedic pathologies are caused by or associated with impairment of systemic or local endochondral ossification. Fractures in the growth-plate (GP) could attenuate endochondral ossification progress, resulting in stunted bone growth whereas diaphyseal fractures in long bones provoke excessive bone growth, presumably due to regional activation of the GP function. In either case, the serious imbalance in bone growth inevitably leads to progressive deformity and significant physical problems. Heterotopic ossification (HO) is another pathological condition driven by ectopic induction of abnormal endochondral ossification. Therapeutic management of the long bone growth and genetic HO requires a long-term, site-specific treatment. Currently there is no drug that has shown adequate therapeutic effectiveness with local administration. During the pre-clinical and clinical studies on the selective nuclear retinoid receptors gamma agonist (RARγ agonist) for HO therapy, we have found that systemic administration of high doses of RARγ agonists causes early closure of GP and inhibits consequent bone growth while RARγ antagonists enhances cartilage growth and delay maturation of GP chondrocytes. These findings led us to hypothesize that RARγ agonists/antagonists may have a marked therapeutic potential for the treatment of conditions involving dysregulated endochondral ossification and bone growth. To this end, we designed nanoparticle (NP) formulations providing controlled release of a potent RARγ agonist. Locally applied drug-loaded NPs showed long retention in muscle and bone, releasing biologically activite RARγ agonist that strongly inhibited ectopic bone formation and logitudinal growth of the targeted bone. Guided by our preliminary results, the current project examines the central hypothesis that RAR γ-specific retinoids formulated in biodegradable nanoparticles for site-specific delivery to the musculoskeletal tissues will effectively control longitudinal growth of the targeted bone and inhibit HO. This hypothesis will be tested by pursuing two specific aims: Aim 1, To develop and characterize the NP-based delivery system for RAR agonists and antagonists; and Aim 2, To determine pharmacological and therapeutic efficacy of these retionid-NPs. The outcomes should provide proof-of-principle for developing novel, nanocarrier-basede drug therapies for HO and for correcting bone growth imbalance that pose an unmet need for new, safer and more effective, treatment strategies.