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

类视黄醇纳米颗粒对软骨内骨化的局部控制

• 批准号: 10238000
• 负责人: Michael Chorny
• 金额: $ 34.53万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-07 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10238000
• 关键词: Address; Adult; Affect; Agonist; Animal Model; Attenuated; BMP2 gene; Biocompatible Materials; Biological; Biological Assay; Biology; Bone Growth; Cartilage; Childhood; Chondrocytes; Clinical; Clinical Research; Collaborations; Deformity; Direct Lytic Factors; Disease; Dose; Drug Delivery Systems; Drug Stability; Effectiveness; Encapsulated; Engineering; Epiphysial cartilage; Formulation; Fracture; Gastrocnemius Muscle; Generations; Genetic; Genetic Suppression; Goals; Growth; Heterotopic Ossification; Histology; Impairment; In Vitro; Inflammatory Response; Injury; Kinetics; Label; Morbidity - disease rate; Mus; Muscle; Musculoskeletal; Musculoskeletal Diseases; Nuclear; Operative Surgical Procedures; Orthopedics; Osteogenesis; Outcome; Pain; Pathologic; Pathology; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Physiologic Ossification; Play; Process; Prodrugs; Production; Quality of life; Regulation; Reporter; Research Personnel; Retinoid Receptor; Retinoids; Site; Skeleton; System; Testing; Therapeutic; Therapeutic Effect; Thick; Tissues; Toxic effect; Transplantation; Treatment Efficacy; Treatment Protocols; Vitamin A; Work; base; bone; controlled release; design; drug candidate; drug testing; effective therapy; in vivo; long bone; matrigel; morphometry; mouse model; multidisciplinary; nanocarrier; nanoparticle; nanoparticle delivery; novel; preclinical study; prevent; repaired; retinoic acid receptor gamma; skeletal; skeletal tissue; soft tissue; spatiotemporal; subcutaneous; success; systemic toxicity; therapeutic effectiveness; tibia; tool; treatment strategy

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.

该项目的目标是开发一种针对软骨内的新型药物治疗策略 时空控制的骨化过程对于软骨内骨化的精确调节至关重要。 它控制儿童时期的正常骨骼形成和生长，是正常骨骼发育所必需的。 成人的骨骼功能和肌肉骨骼修复有多种骨科病理是由或引起的。 与生长板（GP）的全身或局部软骨内骨化损伤有关。 可能会减弱软骨内骨化进程，导致骨生长相对于骨干发育迟缓 长骨骨折会引起骨骼过度生长，这可能是由于 GP 功能的区域激活所致。 无论哪种情况，骨骼生长的严重不平衡都不可避免地导致进行性畸形和严重的畸形。 异位骨化（HO）是由异位诱导引起的另一种病理状况。 长骨生长和遗传性 HO 的异常软骨内骨化需要治疗管理。 目前还没有药物显示出足够的治疗效果。 在选择性核视黄醇受体的临床前和临床研究期间。 γ 激动剂（RARγ 激动剂）用于 H2O2 治疗时，我们发现全身给予高剂量 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 促进软骨生长并延迟 GP 软骨细胞的成熟。这些发现使我们认识到这一点。 RARγ 激动剂/拮抗剂可能对治疗以下疾病具有显着的治疗潜力： 为此，我们设计了纳米颗粒（NP）。 局部应用的载药纳米颗粒可提供有效 RARγ 激动剂的控制释放。 在肌肉和骨骼中长期保留，释放具有生物活性的 RARγ 激动剂，强烈抑制异位 在我们的初步结果的指导下，当前的项目是骨形成和目标骨的纵向生长。 检查了中心假设，即 RAR γ 特异性视黄醇配制在可​​生物降解的纳米颗粒中 用于肌肉骨骼组织的位点特异性递送将有效地控制纵向生长 目标骨并抑制 HO 这一假设将通过追求两个具体目标来检验：目标 1，发展。 并表征基于 NP 的 RARα 激动剂和拮抗剂递送系统；以及目标 2，确定 这些 retionid-NP 的药理学和治疗功效应提供原理证明。 开发新型基于纳米载体的 HO 药物疗法并纠正骨生长失衡 对新的、更安全和更有效的治疗策略的需求尚未得到满足。