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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

基本信息

批准号：
10861426
负责人：
Ambika Goel Bajpayee
金额：
$ 42.26万
依托单位：
NORTHEASTERN UNIVERSITY
依托单位国家：
美国
项目类别：
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

项目摘要

Project Summary/Abstract Osteoarthritis (OA) pain remains an intractable problem with few treatment options. Centrally acting analgesic drugs carry the risk of addictive side effects. Thus, local sustained analgesic delivery is an attractive strategy for development of novel OA pain therapies. Local intra-articular (IA) delivery, however, remains inadequate due to rapid drug clearance from the synovial joint space requiring multiple injections that cause toxicity. This is further complicated by the dense and highly negatively charged cartilage matrix that prevents drugs from reaching their target sites. The parent R01 addressed this challenge by developing cartilage targeting and residing cationic anti-catabolic and pro-anabolic disease modifying OA therapeutics. For example, a receptor antagonist of IL-1 (IL-1RA) was fused with an optimally charged cationic peptide carrier (CPC-IL-1RA), and its effectiveness in suppressing OA associated catabolism was demonstrated in-vitro as well as in vivo with only a one-time dose. Here we will broaden the impact of our work in targeted drug delivery to treatment of OA pain by evaluating the effectiveness in sustained release formulations of (i) cationic fusion CPC-IL-1RA (already developed as part of the parent R01 tasks) and (ii) cationic CCR2 receptor antagonist (CCR2RA). We and others have shown that CCL2/CCR2 signaling is key for promoting persistent pain in the destabilization of the medial meniscus (DMM) model and that its local pharmacological blockade decreases pain behavior. These findings suggest that CCL2- CCR2 signaling locally in the joint also contributes to pain in experimental OA, highlighting the need for developing sustained local delivery methods for CCR2 inhibitors such as CCR2 receptor antagonist (CCR2RA), which is a small molecule. CCR2RA will be fused with a cationic cartilage targeting nano-construct developed for delivery of small molecules, multi-arm Avidin (mAv). The central hypothesis is that a one-time IA injection of CPC-IL-1RA and mAv-CCR2RA will provide sustained analgesic relief over 4 weeks in a rat medial meniscal transection (MMT) OA model. We have a team with expertise in OA pain and in musculoskeletal joint drug delivery that will test this hypothesis in the following aims, Aim 1: Synthesize an intra-cartilage depot for a month- long sustained release of CCR2RA using cationic mAv using hydrolysable ester linkers. Drug release rates and bioactivity of the conjugate will be measured and compared with unmodified drug in-vitro. Aim 2: Test the efficacy of a single IA injection of cationic CPC-IL-1RA and mAv-CCR2RA in the rat MMT model. Male and female rats will receive an IA injection of saline, CPC-IL-1RA, unconjugated IL-1RA, mAv-CCR2RA, or unconjugated CCR2RA. Weight-bearing asymmetry and knee hyperalgesia will be assessed; DRG changes will be evaluated by IHC and RNAscope; joint histopathology will be assessed, including assessment of knee innervation changes and immune cell infiltration. This competitive urgent revision will broaden the impact of the already designed cationic therapeutics for sustained OA pain suppression over a month with only a single IA administration thereby providing long-term pain relief, in addition to disease modification (which was addressed in the original R01).

项目摘要/摘要骨关节炎(OA)疼痛仍然是一个难以解决的问题，几乎没有治疗选择。中枢作用止痛药毒品有可能产生上瘾的副作用。因此，局部持续给予止痛药是一种有吸引力的治疗策略新的骨性关节炎疼痛疗法的开发。然而，由于以下原因，局部关节内(IA)分娩仍然不够药物从滑膜关节间隙迅速清除，需要多次注射才能引起毒性。这是更远的复杂的致密和高度负电的软骨基质，阻止药物到达他们的目标站点。母体R01通过发展软骨靶向和驻留阳离子来解决这一挑战抗分解代谢和促合成代谢疾病改变了骨关节炎的治疗方法。例如，IL-1的受体拮抗剂 (IL-1RA)与最佳带电阳离子多肽载体(CPC-IL-1RA)融合，并观察其在体内的作用。在体外和体内，仅一次给药即可抑制OA相关的分解代谢。在这里，我们将扩大我们在靶向给药方面的工作对治疗骨性关节炎疼痛的影响，方法是评估 (I)阳离子融合CPC-IL-1RA(已作为亲本R01的任务)和(Ii)阳离子CCR2受体拮抗剂(CCR2RA)。我们和其他人已经证明了 CCL2/CCR2信号通路在促进内侧半月板失稳(DMM)持续性疼痛中起关键作用模型和其局部药理阻断可减少疼痛行为。这些发现表明，CCL2- 关节局部的CCR2信号也与实验性骨性关节炎的疼痛有关，强调了开发CCR2抑制剂如CCR2受体拮抗剂(CCR2RA)的持续局部给药方法，这是一个小分子。CCR2RA将与开发的靶向纳米结构的阳离子软骨融合用于运送小分子的多臂亲和素(MAV)。中心假设是一次性注射IA CPC-IL-1RA和MAV-CCR2RA对大鼠内侧半月板的持续镇痛作用超过4周横断(MMT)骨性关节炎模型。我们有一支在骨性关节炎疼痛和肌肉骨骼关节药物方面拥有专业知识的团队将在以下目标中检验这一假设的交付，目标1：在一个月内合成一个软骨内仓库- 使用阳离子MAV和可水解酯连接物的CCR2RA的长期持续释放。药物释放率和体外测定偶联物的生物活性，并与未修饰药物进行比较。目标2：测试疗效单次IA注射阳离子CPC-IL-1RA和MAV-CCR2RA建立大鼠MMT模型。雄性和雌性大鼠将接受生理盐水、CPC-IL-1RA、未结合的IL-1RA、MAV-CCR2RA或未结合的IA注射 CCR2RA。将评估负重不对称和膝关节痛觉过敏；将评估DRG的变化由IHC和RNAScope进行关节组织病理学评估，包括膝关节神经变化的评估和免疫细胞的渗透。这一竞争性的紧急修订将扩大已经设计的阳离子疗法持续抑制骨性关节炎疼痛超过一个月，因此只需一次IA治疗提供长期的疼痛缓解，除了疾病修改(这在最初的R01中提到)。