Bioerodible corticosteroid microparticle-drug as an intra-articular drug delivery system for osteoarthritis therapy

可生物侵蚀的皮质类固醇微粒药物作为骨关节炎治疗的关节内药物递送系统

• 批准号: 10709663
• 负责人: Omolola Eniola-Adefeso
• 金额: $ 25.83万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-23 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10709663
• 关键词: Acute; Adrenal Cortex Hormones; Adult; Affect; Age; Analgesics; Anti-Inflammatory Agents; Attention; Automobile Driving; Cartilage; Cells; Characteristics; Chondrocytes; Chronic; Clinical; Clinical Management; Clinical Treatment; Data; Degenerative polyarthritis; Disease; Dose; Drug Delivery Systems; Exhibits; Exposure to; Extracellular Matrix; Fibroblasts; Foreign Bodies; Formulation; Gene Expression; Geometry; High Pressure Liquid Chromatography; Immune; In Vitro; Inflammation; Inflammatory; Injections; Injury; Intra-Articular Injections; Joints; Kinetics; Length; Literature; Macrophage; Maintenance; Measures; Metabolic Clearance Rate; Metals; Methods; Methylprednisolone; Methylprednisolone Sodium Succinate; Morphology; Mus; Nuclear Magnetic Resonance; Pain; Pathogenicity; Peptide Hydrolases; Pharmaceutical Preparations; Placebos; Polymers; Process; Production; Proliferating; Property; Replacement Arthroplasty; Reporting; Rod; Role; Scanning Electron Microscopy; Shapes; Sodium Chloride; Steroids; Structure; Succinates; Surface; Synovitis; System; T-Lymphocyte; Testing; Therapeutic; Therapeutic Effect; Time; Tissues; Treatment Efficacy; Water; Work; arthropathies; bile salts; biodegradable polymer; cell type; chemokine; chronic pain; clinically relevant; controlled release; cyanine dye 5; cytokine; disability; fabrication; fluorophore; high reward; high risk; improved; in vivo; in vivo fluorescence; inflammatory modulation; joint destruction; joint inflammation; joint injury; meter; mouse model; nanoGold; nanoparticle; negative affect; novel; osteoarthritis pain; pain reduction; pain relief; palliative; particle; protein expression; response; side effect; small molecule; solute; standard care; tissue degeneration; uptake

Abstract Osteoarthritis (OA) is one of the world’s leading causes of disability. About ~27 million adults in the U.S. have symptomatic OA and suffer from chronic pain for several decades. Current clinical management of OA is entirely palliative, and the definitive end-stage management is total joint arthroplasty. Consequently, there exists an immediate and critical need to develop novel treatments that improve chronic pain and disability in OA. Intra-articular corticosteroids have shown benefit over placebo in OA across all ages due to their ability to reduce pain and mitigate joint inflammation. However, their efficacy is short-lived and is associated with dose- dependent deleterious effects. We recently reported that therapeutic microparticles with the active drug comprising near 100% of the particle’s matrix, i.e., no exogenous polymer, can be achieved via a gold- nanoparticle templating method. Using this approach, this proposal seeks to develop corticosteroid-derived microparticles for the intra-articular treatment of OA. We hypothesize that erodible particles that consist almost entirely of the active drug molecules (>90%) will offer a controlled release of corticosteroids locally in the diseased joint for an extended period, effectively reducing the pain and inflammation in OA while avoiding adverse side effects associated with high doses, multiple treatments, and the use of exogenous biodegradable polymers. Specifically, we will explore the fabrication of methylprednisolone succinate sodium salt (MPS) particles by modifying our novel metal-nanoparticle templating method, which we have demonstrated for generating composite bile salt particle that enables fine-tuned, controlled release of therapeutically active bile salt. We will first mechanistically uncover how the fabrication parameters affect MPS-drug particle formation, geometry, and erosion characteristics while also confirming long-term intra-articular retention (Aim 1). We will then evaluate the anti-inflammatory capacity of the generated corticosteroid microparticles in vitro using OA- relevant cell types, assessing modulation of inflammatory gene and protein expression. We will confirm that corticosteroid particles have minimal deleterious effects on chondrocyte viability, proliferation, and extracellular matrix maintenance (Aim 2.1). We will then evaluate the therapeutic efficacy of the novel corticosteroid microparticles to control inflammation and pain in vivo using a clinically relevant mouse model of joint injury- induced OA (Aim 2.2). Overall, the proposed work, if successful, can make transformative progress towards the clinical treatment of OA and other joint disorders by providing a more efficacious and longer-lasting intra- articular analgesic therapy.

摘要 骨关节炎（OA）是世界上主要的残疾原因之一。美国大约有2700万成年人 症状性OA，并遭受数十年的慢性疼痛。目前OA的临床管理是 完全姑息，最终的治疗方法是全关节置换术。因此，在 目前迫切需要开发新的治疗方法，以改善慢性疼痛和残疾， OA。关节内皮质类固醇在所有年龄段的OA中均显示出优于安慰剂的获益，因为其能够 减轻疼痛和减轻关节炎症。然而，它们的功效是短暂的，并且与剂量有关。 依赖的有害影响。我们最近报道了含有活性药物的治疗性微粒 包括接近100%的颗粒基质，即，没有外源聚合物，可以通过金- 纳米粒子模板法使用这种方法，该提议寻求开发皮质类固醇衍生的 用于OA的关节内治疗的微粒。我们假设， 几乎全部的活性药物分子（>90%）将在局部提供皮质类固醇的控制释放， 有效地减轻OA的疼痛和炎症，同时避免 与高剂量、多次治疗和使用外源性可生物降解药物相关的不良副作用 聚合物具体来说，我们将探索甲基强的松龙琥珀酸钠盐（MPS）的制造 粒子通过修改我们的新的金属纳米粒子模板的方法，我们已经证明， 产生能够微调、控制释放治疗活性胆汁的复合胆汁盐颗粒 盐我们将首先从机械上揭示制造参数如何影响MPS药物颗粒的形成， 几何形状和侵蚀特征，同时也证实了长期关节内固位（目标1）。我们将 然后使用OA-100在体外评价所产生的皮质类固醇微粒的抗炎能力。 相关细胞类型，评估炎症基因和蛋白质表达的调节。我们将确认， 皮质类固醇颗粒对软骨细胞的活力、增殖和细胞外基质具有最小的有害作用。 矩阵维护（目标2.1）。然后我们将评估新的皮质类固醇的治疗效果 使用关节损伤的临床相关小鼠模型， 诱导OA（目标2.2）。总的来说，拟议的工作如果成功，可以取得变革性进展， OA和其他关节疾病的临床治疗，通过提供更有效和更持久的内， 关节止痛疗法