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.

项目总结 创伤后骨关节炎(PTOA)是关节损伤的一种潜在后果，约50%的膝关节损伤患者- 受伤后10年内表现为创伤后应激障碍。目前，PTOA尚无治愈方法，但PTOA的急性性质 突发性损伤为PTOA治疗提供了一种独特的方法：靶向预防性药物 采取干预措施，以减轻/预防损伤后疾病的发生。许多有针对性的临床前研究 已经进行了治疗。然而，由于极快的关节内(i.a.)毒品清除，疾病- 改变药物效率是非常有限的，需要反复大剂量地给予免费药物才能有效。 给出内务部的低效。免费给药，延长药物滞留时间的给药方法 通过靶向受伤关节的组织可以代表一种具有成本效益的方法来增加治疗 功效。我们提出了一种新颖而通用的平台，用于热响应、本地化的候选递送 PTOA药物用于损伤的关节，以限制PTOA的启动/进展。我们的方法依赖于我们的开拓性 弹性蛋白-胶原-多肽结合物的开发，这种结合物独特地形成载货纳米囊泡，从而促进 在体温下长期被动释放和在轻度低温下加速/猝发分娩 温度。此外，构成囊泡外壳的类胶原肽可以靶向变性 胶原蛋白，使胶原蛋白损伤/重塑增加的组织中堆积。 在这项提案中，我们将评估候选PTOA疾病修改药物的加载情况(重点是 地塞米松)在精制弹性蛋白-胶原纳米囊泡(ECnV)中，并监测其稳定性以及 被动和低温触发的药物释放。幼稚和“损伤/激活”软骨细胞的研究， 滑膜成纤维细胞、单核/巨噬细胞、关节软骨和滑膜组织移植 确认细胞/生物相容性，并量化地塞米松负载的ECNV对损伤标记物的抑制。我们 将使用PTOA的无创重复关节加载(过度使用)模型进行体内实验 显示关节内损伤后ECNV的选择性滞留。注射。多尺度 体内、原位和组织学/免疫组织化学分析将被用来评估 被动和低温引发的货物释放的药物动力学，组织定位/生物分布， 以及ECNV对健康和早期PTOA关节的局部和系统生物相容性/安全性。 最后，我们将表征基于ECnV的Dex递送改善疾病修改生理的能力 在上述非侵入性关节损伤模型中，PTOA的结果是预防性的。 脂质体和游离地塞米松治疗作为对照。虽然拟议的工作重点是增加 PTOA治疗的有效性，也为使用胶原靶向ECnV药物载体奠定了基础 涵盖以异常胶原蛋白重塑为特征的多种疾病和病理。