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: 10472544
• 负责人: Michael Chorny
• 金额: $ 35.25万
• 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 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10472544
• 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; antagonist; 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.

该项目的目的是制定一种针对内侧软骨的新型药物治疗策略 时空对照的骨化过程。精确调节内软骨骨化是必不可少的 肌肉骨骼组织。它在童年时期变为正常的骨骼形成和生长，是正确的 成人的骨骼功能和肌肉骨骼修复。多种骨科病理是由或 与全身或局部内软骨骨化受损有关。生长板（GP）中的断裂 可能减弱内软骨骨化进展，导致骨骼发育迟缓，而糖尿病 长骨骼中的裂缝会刺激超过骨骼生长，这大概是由于GP功能的区域激活。 无论哪种情况，骨骼生长的严重失衡都不可避免地导致逐渐畸形和显着 身体问题。异位骨化（HO）是另一个由依托诱导驱动的病理状况 异常内软骨骨化。长骨生长和遗传HO的治疗管理需要 长期，特定于现场的治疗。目前没有药物表现出足够的治疗效果 与地方管理。在临床前和临床研究中，关于选择性核性类维生素类受体 伽玛激动剂（RARγ激动剂）用于HO治疗，我们发现全身给药高剂量 RARγ厌氧菌会引起GP的早期关闭，并抑制随后的骨骼生长 增强软骨生长和GP软骨细胞的延迟成熟。这些发现使我们假设 RARγ激动剂/拮抗剂可能具有明显的治疗潜力，以治疗涉及的疾病 内侧软骨骨化和骨骼生长失调。为此，我们设计了纳米颗粒（NP） 提供了潜在的RARγ激动剂的控制释放的公式。局部施用的药物负载的NP 长期保持在肌肉和骨骼中，释放生物学上的激活岩RARγ激动剂，该激动剂强烈抑制了生态 靶骨的骨形成和逻辑生长。在我们的初步结果的指导下，当前项目 研究了中心假设，即在可生物降解的纳米颗粒中配制的RARγ特异性类维生素类似 对于特定于部位向肌肉骨骼组织的递送将有效控制 靶骨并抑制HO。该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rar激动剂和拮抗剂的传递系统；和目标2，以确定 这些RetionId-NP的药理和治疗效率。结果应提供原理证明 用于开发用于HO的新型，基于纳米载体的药物疗法，并纠正骨骼生长失衡 对新的，更安全，更有效的治疗策略构成了未满足的需求。

项目成果

Selective Retinoic Acid Receptor γ Antagonist 7C is a Potent Enhancer of BMP-Induced Ectopic Endochondral Bone Formation.

• DOI: 10.3389/fcell.2022.802699
• 发表时间: 2022
• 期刊: Frontiers in cell and developmental biology
• 影响因子: 5.5
• 作者: Tateiwa D;Kaito T;Hashimoto K;Okada R;Kodama J;Kushioka J;Bal Z;Tsukazaki H;Nakagawa S;Ukon Y;Hirai H;Tian H;Alferiev I;Chorny M;Otsuru S;Okada S;Iwamoto M
• 通讯作者: Iwamoto M