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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要创伤后骨关节炎 (PTOA) 是关节损伤的潜在后果，约 50% 的膝关节损伤患者损伤后 10 年内出现 PTOA 目前尚无治疗 PTOA 的方法，但其急性性质。突发性损伤提供了一种独特的 PTOA 治疗方法：靶向预防性药物减轻/预防损伤后疾病发生的干预措施许多有针对性的临床前研究。然而，由于关节内（i.a）药物清除速度极快，疾病- 改变药物功效非常有限，需要重复高剂量施用游离药物才能发挥功效。给出 i.a. 给药、延长药物停留时间的递送方法的低效率通过针对受伤关节的组织可能是一种具有成本效益的增加治疗的方法我们提出了一种新颖且多功能的平台，用于热响应、局部递送候选物。对受伤关节使用 PTOA 药物来限制 PTOA 的发生/进展我们的方法依赖于我们的开拓性。开发弹性蛋白-胶原蛋白-肽缀合物，独特地形成负载货物的纳米囊泡，促进在体温下长期被动释放，在轻度低温下加速/突发释放此外，构成囊泡外壳的类胶原蛋白肽可以靶向变性。胶原蛋白，允许胶原蛋白损伤/重塑增加的组织中积累。在本提案中，我们将评估候选 PTOA 疾病缓解药物的载量（重点是在精制弹性蛋白胶原纳米囊泡 (ECnV) 中加入地塞米松 (Dex) 并监测其稳定性，以及对幼稚和“受伤/激活”软骨细胞的被动和低温触发药物释放的研究，滑膜成纤维细胞、单核细胞/巨噬细胞、关节软骨和滑膜组织外植体，将确认细胞/生物相容性并量化 Dex 负载的 ECnV 对“损伤”标记的抑制。将使用 PTOA 的非侵入性重复关节负荷（过度使用）模型进行体内实验证明多尺度注射后 ECnV 在受伤关节内的选择性保留。将采用体内、原位和组织学/免疫组织化学分析来评估被动和低温触发的货物释放的药代动力学、组织定位/生物分布、以及 ECnV 传递到健康和早期 PTOA 关节的局部和全身生物相容性/安全性。最后，我们将描述基于 ECnV 的 Dex 递送改善疾病缓解生理学的能力和 PTOA 在上述非侵入性关节损伤模型中的预防性结果，具有标准 i.a. 尽管拟议的工作重点是增加脂质体和游离 Dex 治疗。 PTOA治疗效果，也将为胶原蛋白靶向ECnV药物载体的使用奠定基础涵盖以异常胶原蛋白重塑为特征的广泛疾病和病理学。