Intra-cartilage depot delivery of electrically-charged IL-1RA for targeting osteoarthritis-associated inflammation and catabolism in multiple joint tissues

软骨内储库递送带电 IL-1RA，用于靶向多个关节组织中与骨关节炎相关的炎症和分解代谢

• 批准号: 10471429
• 负责人: Ambika Goel Bajpayee
• 金额: $ 42.12万
• 依托单位: NORTHEASTERN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-21 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10471429
• 关键词: Acceleration; Adverse effects; Affect; Affinity; Anabolism; Arthritis; Avidin; Binding; Biochemical; Biodistribution; Biological; Biotinylation; Bone callus; Bovine Cartilage; Cartilage; Cartilage Matrix; Catabolism; Cell Survival; Cells; Charge; Clinical Trials; Coculture Techniques; Collagen; Confocal Microscopy; Degenerative polyarthritis; Diameter; Disease; Dose; Drug Carriers; Drug Delivery Systems; Drug Modulation; Drug or chemical Tissue Distribution; Effectiveness; Electrostatics; Engineering; Equilibrium; Fracture; Gene Expression; Genes; Glycoproteins; Glycosaminoglycans; Histology; Immunohistochemistry; In Vitro; Inflammation; Inflammatory; Injury; Interleukin-1; Interleukins; Intervertebral disc structure; Intra-Articular Injections; Joints; Label; Mass Spectrum Analysis; Measures; Mediating; Meniscus structure of joint; MicroRNAs; Modeling; Modification; Organ; Oryctolagus cuniculus; Outcome; Penetration; Peptides; Pharmaceutical Preparations; Pre-Clinical Model; Property; Proteins; Proteomics; Radiolabeled; Rattus; Role; Site; Specificity; Structure; Synovial Fluid; Synovial Membrane; Synovial joint; Synovitis; Techniques; Testing; Therapeutic; Thick; Time; Tissues; Traumatic Arthropathy; Western Blotting; Work; anakinra; articular cartilage; biomechanical test; bone; cellular targeting; clinical effect; clinical translation; cytokine; density; design; driving force; drug clearance; effective therapy; exosome; extracellular; in vivo; inhibitor; joint injury; microCT; prevent; protein expression; residence; response; subchondral bone; systemic toxicity; targeted delivery; time use; tissue degeneration; uptake

Project Summary Despite the existence of promising osteoarthritis (OA) drugs, its treatment remains a challenge due to ineffective drug delivery systems. Intra-articular (IA) delivery is inadequate as drugs rapidly clear out from joint space and are unable to penetrate through the dense, negatively charged cartilage and reach their cell and matrix target sites at optimal concentrations. As a result, no disease modifying OA drugs (DMOADs) have passed clinical trials due to concerns of systemic toxicity and lack of cartilage targeting. For effective treatment, it is critical to stimulate a disease modifying biological response within multiple joint tissues, including cartilage, synovium and subchondral bone. Interleukin (IL)-1 receptor antagonist (IL-1RA) is proven to be a promising DMOAD for modulating both synovium inflammation and cartilage catabolism in preclinical models of post-traumatic (PT)OA; however, it has failed to show sustained clinical effect owing to lack of cartilage targeting and short joint residence time. The high negative charge density of cartilage provides a unique opportunity to use electrostatic interactions for enhancing uptake, depth of penetration, and retention of cationic drugs or drug carriers. We have shown that the cationic glycoprotein Avidin, owing to its optimal size and charge, was effective for intra-cartilage delivery as it rapidly penetrated through full thickness of cartilage in rats and rabbits following IA injection, resulting in 400- fold higher intra-cartilage uptake compared to its neutral counterpart and was retained inside cartilage for 3-4 weeks. Based on Avidin’s structure, we have designed a Cationic Peptide Carrier (CPC) that displayed similarly high uptake in both normal and glycosaminoglycan-depleted cartilage. This project will develop electrically charged IL-1RA by conjugating it with Avidin and CPC to make it cartilage penetrating and binding, thus increasing its tissue specificity and residence time. This way, cartilage can be converted from a barrier to drug entry into a drug depot, such that the anti-catabolic effects of charged IL-1RA in both cartilage and nearby synovium are significantly enhanced compared to unmodified IL-1RA. In Aim 1, Avidin-IL-1RA and CPC-IL-1RA will be characterized and their key transport properties (diffusivities, equilibrium uptakes, partitioning, binding constants) will be compared with unmodified IL-1RA in normal and arthritic cartilage. Aim 2 will evaluate the biological efficacy of a single dose of charged IL-1RA for inhibiting cytokine induced catabolism in a cartilage- synovium co-culture OA model, comparing Avidin/CPC-IL-1RA conjugates with single and continuous dose of unmodified IL-1RA. Aim 3 will determine the therapeutic potential of a single IA injection of charged IL-1RA relative to unmodified IL-1RA using a rabbit PTOA model. This work will advance the field of charge based drug delivery in targeting multiple joint tissues for effective, holistic OA treatment by applying fundamental concepts of bio-electrostatics and bio-transport. This charge-based platform can be used for delivering a wide range of drugs to other tissues with similar properties, such as meniscus, intervertebral disc and fracture callus, and also enable clinical translation of various OA drugs that have failed clinical trials due to lack of tissue targeting.

项目摘要 尽管存在承诺的骨关节炎（OA）药物，但由于无效，其治疗仍然是一个挑战 药物输送系统。关节内（IA）的递送不足，因为药物从关节空间和 无法穿透密集的，带负电荷的软骨并到达其细胞和矩阵目标 最佳浓度的地点。结果，没有修改OA药物（DMOADS）通过临床 由于担心系统性毒性和缺乏软骨靶向的试验。对于有效的治疗，至关重要 刺激疾病改变多个关节组织中的生物学反应，包括软骨，滑膜和 软骨下骨。白介素（IL）-1受体拮抗剂（IL-1RA）被证明是有希望的DMOAD 在创伤后（PT）OA的临床前模型中调节滑膜注射和软骨分解代谢； 但是，由于缺乏软骨靶向和较短的关节居住，它未能显示出持续的临床效果 时间。软骨的高电荷密度为使用静电相互作用提供了独特的机会 为了增强阳离子药物或药物载体的摄取，渗透深度和保留。我们已经表明 由于其最佳尺寸和电荷，阳离子糖蛋白抗生物素可有效地递送。 IA注射后，它通过大鼠和兔子的软骨厚度迅速穿透，导致400- 与中性同等相比，折叠较高的 - 运动内摄取的摄取，并在软骨内保留3-4 几周。根据Avidin的结构，我们设计了一个类似显示的阳离子肽载体（CPC） 在正常和糖胺聚糖的软骨中均高吸收。该项目将电气发展 通过将AVIDIN和CPC偶联来使IL-1RA充电，使其软骨穿透和结合，因此 增加其组织特异性和停留时间。这样，软骨可以从障碍物转换为药物 进入药物仓库，使带电IL-1RA在软骨和附近的抗代谢作用 与未修饰的IL-1RA相比，滑膜显着增强。在AIM 1，Avidin-IL-1RA和CPC-IL-1RA中 将被表征及其关键运输特性（扩散性，平衡吸收，分配，结合 常数将与未修饰的IL-1RA进行比较，在正常和艺术软骨中。 AIM 2将评估 单剂量带电IL-1RA的生物学效率用于抑制软骨中细胞因子诱导的分解代谢 Synovium共培养OA模型，将Avidin/CPC-IL-1RA偶联物与单一和连续剂量进行比较 未修饰的IL-1RA。 AIM 3将确定单个IA注入带电IL-1RA的治疗潜力 使用兔PTOA模型相对于未修饰的IL-1RA。这项工作将推进基于费用的药物领域 通过应用基本概念来靶向多个关节组织以有效，整体OA处理 生物电子统计学和生物传播。此基于电荷的平台可用于提供广泛的 药物对具有相似特性的其他组织，例如弯月面，椎间盘和断裂愈伤组织，也是 由于缺乏组织靶向，使各种OA药物的临床翻译能够临床试验失败。