Collagen-mediated approaches to improve the local delivery and hypothermic release of osteoarthritis therapeutics

胶原介导的方法改善骨关节炎治疗药物的局部递送和低温释放

• 批准号: 10595325
• 负责人: Kristi L Kiick
• 金额: $ 63.79万
• 依托单位: UNIVERSITY OF DELAWARE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10595325
• 关键词: Acceleration; Acute; Affect; Binding; Biodistribution; Biological; Body Temperature; Bone structure; Cartilage; Cells; Chondrocytes; Clinical; Clinical Treatment; Collagen; Consultations; Cumulative Trauma Disorders; Degenerative polyarthritis; Development; Dexamethasone; Disease; Disease Management; Disease Progression; Dose; Doxycycline; Drug Carriers; Drug Controls; Drug Delivery Systems; Drug Kinetics; Drug Targeting; Effectiveness; Elastin; Etiology; Exhibits; Extracellular Matrix; Fibroblasts; Foundations; Histologic; In Situ; In Vitro; Inflammation; Injury; Intervention; Intra-Articular Injections; Investigation; Joints; Knee Injuries; Knee joint; Label; Letters; Lipids; Liposomes; Macrophage; Matrix Metalloproteinase Inhibitor; Mediating; Methods; Microscopy; Minerals; Modeling; Modification; Monitor; Mus; Nature; Outcome; Pathology; Patients; Peptides; Pharmaceutical Preparations; Pharmacologic Substance; Physiology; Polymers; Prevention; Price; Safety; Spectrum Analysis; Strontium; Synovial Fluid; Temperature; Testing; Therapeutic; Time; Tissues; Traumatic Arthropathy; Treatment Efficacy; Vesicle; Work; anakinra; analog; anterior cruciate ligament rupture; articular cartilage; biomaterial compatibility; cell injury; controlled release; cost; cost effective; design; drug candidate; drug clearance; drug efficacy; experimental study; immunogenicity; improved; in vivo; injured; joint inflammation; joint injury; joint loading; light scattering; meniscal tear; monocyte; nanoparticle; nanovesicle; natural hypothermia; novel; palliative; pre-clinical; preclinical study; preservation; prevent; programs; prophylactic; residence; targeted delivery; targeted treatment; therapeutic candidate; translational potential; translational therapeutics

PROJECT SUMMARY Post-traumatic osteoarthritis (PTOA) is an insidious consequence of joint injury, ~50% of patients with knee- injuries exhibit PTOA within 10-years of injury. Presently, no cure for PTOA exists, but the acute nature of the precipitating injuries provides for a unique approach to PTOA treatment: targeted prophylactic pharmaceutical intervention to mitigate/prevent the initiation of disease post-injury. Many pre-clinical investigations for targeted treatment have been conducted. However, due to incredibly rapid intra-articular (i.a.) drug clearance, disease- modifying drug efficiency is highly limited, requiring repeated high-dose administration of free drug for efficacy. Give the inefficiencies of i.a. administration of free drug, delivery approaches that extend drug-residence time by targeting the tissues of the injured joint could represent a cost-effective method of increasing therapeutic efficacy. We propose a novel and versatile platform for the thermally responsive, localized delivery of candidate PTOA drugs to injured joints to limit initiation/progression of PTOA. Our approach relies on our pioneering development of elastin-collagen-peptide conjugates that uniquely form cargo-laden nanovesicles that facilitate long-term passive release at body temperature and accelerated-/burst-delivery at mildly hypothermic temperatures. In addition, the collagen-like peptides comprising the vesicle’s outer ‘shell’ can target denatured collagens, allowing accumulation in tissues with elevated collagen damage/remodeling. In this proposal, we will evaluate the loading of candidate PTOA disease-modifying drugs (with a focus on dexamethasone (Dex)) in refined elastin-collagen nano-vesicles (ECnV) and monitor their stability, as well as passive and hypothermally-triggered drug release. Studies on naïve and ‘injured/activated’ chondrocytes, synovial fibroblasts, and monocyte/macrophages, and articular cartilage and synovial tissue explants, will confirm the cyto-/biocompatibility and quantify the suppression of ‘injury’ markers by Dex-loaded ECnVs. We will conduct in vivo experiments using a non-invasive repeated joint loading (overuse) model of PTOA to demonstrate the selective retention of ECnVs within injured joints after intra-articular (i.a.) injection. Multi-scale in vivo, in situ, and histological/immunohistochemical analyses will be employed to evaluate the pharmacokinetics of passively and hypothermally-triggered cargo release, tissue localization/biodistribution, and the local and systemic biocompatibility/safety of ECnVs delivered to both healthy and early-PTOA joints. Finally, we will characterize the ability of ECnV-based delivery of Dex to improve disease-modifying physiology and PTOA outcomes prophylactically in the aforementioned non-invasive, joint injury model, with standard i.a. liposomal and free-Dex treatments serving as comparators. Although the proposed work focuses on increasing PTOA therapy effectiveness, it will also lay a foundation for the use of collagen-targeting ECnV drug carriers across a broad range of diseases and pathologies characterized by aberrant collagen remodeling.

项目摘要 创伤后骨关节炎（PTOA）是关节损伤的阴险后果，膝关节患者中有50％ 伤害在受伤后的10年内暴露了PTOA。目前，无法治愈PTOA，而是 沉淀损伤为PTOA治疗提供了独特的方法：靶向预防药物 干预以减轻/防止伤害后疾病的倡议。许多针对目标的临床前研究 已经进行了治疗。但是，由于关节内（I.A.）药物清除率非常快，疾病 - 修改药物效率高度有限，需要重复高剂量的游离药物以提高效率。 给予I.A.的效率低下延长毒品居住时间的免费药物，递送方法 通过靶向受伤关节的组织，可以代表一种成本效益的方法来增加治疗 功效。我们提出了一个新颖且多功能的平台，用于热响应的候选人的局部局部交付 PTOA药物可受伤的关节，以限制PTOA的主动性/进展。我们的方法取决于我们的开拓 弹性蛋白 - 胶原肽的开发结合物，形成促进货物的纳米层的独特 在体温下长期被动释放，并在轻度低温下加速/爆发分发 温度。此外，完成囊泡的外壳“外壳”的类似胶原蛋白的宠物可以定为变性 胶原蛋白，可以在胶原蛋白损伤/重塑升高的组织中积聚。 在此提案中，我们将评估候选PTOA疾病改良药物的负载（重点是） 精致的弹性蛋白 - 胶原纳米壁画（ECNV）中的地塞米松（DEX））并监测其稳定性 被动和低温触发的药物释放。关于幼稚和“受伤/活化”软骨细胞的研究， 滑膜成纤维细胞，单核细胞/巨噬细胞以及关节软骨和滑膜组织外植体将 确认细胞/生物相容性，并通过DEX负载的ECNV量化“伤害”标记。我们 将使用PTOA的非侵入性重复关节载荷（过度使用）进行体内实验 表明关节内（I.A.）注射后受伤的关节内ECNV的选择性保留。多尺度 体内，原位和组织学/免疫组织化学分析将被雇用以评估 被动和低温触发的货物释放，组织定位/生物分布的药代动力学， ECNV的局部和系统生物相容性/安全性都交付给了健康和早期关节。 最后，我们将表征基于ECNV的DEX改善疾病改良生理学的能力 在近似非侵入性的关节损伤模型中，具有预防性的PTOA结局，具有标准I.A. 脂质体和自由饮用治疗作为比较剂。尽管拟议的工作重点是增加 PTOA疗法有效性，它将为使用胶原蛋白的ECNV药物载体奠定基础 在广泛的疾病和病理中，以异常胶原蛋白的重塑为特征。