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

本项目的目标是开发一种新的靶向软骨内分泌的药物治疗策略。 具有时空控制的骨化过程。对软骨内骨化的精确调节是至关重要的， 肌肉骨骼组织它在儿童时期维持正常的骨骼形成和生长， 骨骼功能和肌肉骨骼修复。各种骨科疾病是由或 与全身或局部软骨内骨化受损相关。生长板骨折（GP） 可以减弱软骨内骨化进程，导致骨生长发育迟缓，而骨干 长骨骨折引起骨过度生长，推测是由于GP功能的局部激活。 在任何一种情况下，骨生长的严重不平衡不可避免地导致进行性畸形和显著的 身体问题。异位骨化（HO）是由异位诱导骨化引起的另一种病理状况。 异常的软骨内骨化长骨生长和遗传HO的治疗管理需要 一种长期的针对性治疗目前还没有药物显示出足够的治疗效果 与当地政府。在选择性核维甲酸受体的临床前和临床研究中， 我们已经发现，全身给予高剂量的RARγ激动剂， RARγ激动剂导致GP早期关闭并抑制随后的骨生长，而RARγ拮抗剂 增强软骨生长并延迟GP软骨细胞的成熟。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，用于治疗涉及RAR γ激动剂/拮抗剂的病症。 软骨内骨化和骨生长失调。为此，我们设计了纳米粒子（NP） 提供有效RARγ激动剂的受控释放的制剂。局部应用的载药纳米粒显示， 在肌肉和骨骼中长时间保留，释放具有生物活性的RARγ激动剂，强烈抑制异位 骨形成和靶骨的对数生长。根据我们的初步结果，目前的项目 检查了中心假设，即在可生物降解的纳米颗粒中配制的RAR γ特异性维甲酸 用于位点特异性递送至肌肉骨骼组织将有效地控制 靶向骨并抑制HO。这一假设将通过追求两个具体目标来检验：目标1， 并表征用于RAR β激动剂和拮抗剂的基于NP的递送系统;以及目的2，确定 这些类维生素A-NP的药理学和治疗功效。结果应提供原则证明 用于开发用于HO的新的、基于纳米载体的药物疗法和用于校正骨生长不平衡， 对新的、更安全和更有效的治疗策略提出了未满足的需求。

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.