Nonaddictive opioid prodrug nanomedicine for musculoskeletal pain

用于治疗肌肉骨骼疼痛的非成瘾性阿片类药物前体纳米药物

基本信息

批准号：
10700168
负责人：
Dong Wang
金额：
$ 47.84万
依托单位：
UNIVERSITY OF NEBRASKA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-07 至 2027-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10700168
关键词：
Absence of pain sensation Acute Pain Address Analgesics Behavior Benchmarking Biodistribution Blood Bone callus Brain Cell physiology Cells Chronic Circulation Clinical Closed Fractures Data Degenerative polyarthritis Dependence Development Dimensions Drug Addiction Drug Kinetics Experimental Models Femoral Fractures Formulation Functional disorder Gel Glucocorticoids Hydrogels Hydromorphone In Vitro Inflammation Inflammatory Kidney Kinetics Liquid substance Mechanics Medial meniscus structure Mediating Medication Management Modeling Modification Molecular Weight Mus Musculoskeletal Musculoskeletal Diseases Musculoskeletal Pain Non-Steroidal Anti-Inflammatory Agents Operative Surgical Procedures Opiate Addiction Opioid Orthopedics Pain Pain management Pathology Phagocytes Phase Transition Physiological Physiology Postoperative Pain Postoperative Period Prodrugs Property Risk Safety Series Site Spinal Cord Surgeon Surgical Specialties Surveys Testing Time Tissues Translations Trauma Traumatic Arthropathy Weight addiction aqueous bone fracture repair candidate selection chronic pain clinical practice copolymer design efficacy evaluation efficacy testing in vivo in vivo optical imaging injury and repair methacrylamide mouse model musculoskeletal injury nanomedicine novel opioid epidemic opioid mortality optical imaging osteoarthritis pain pain relief repaired safety assessment side effect skeletal skeletal injury

项目摘要

ABSTRACT Musculoskeletal disorders are among the most common causes of acute and chronic pain. Extensive use of opioids for these conditions has made a substantial contribution to the current opioid epidemic. There is an urgent need to develop potent analgesics that are as effective as opioids but avoids the side effects, including the risk of dependency and addiction. To address this challenge, we have developed a macromolecular prodrug (P-HMP) of hydromorphone (HMP) based on N-(2-hydroxypropyl) methacrylamide (HPMA) copolymers. When HMP content increased to ³ 16 wt%, the aqueous solution of P-HMP becomes thermoresponsive and transitions from a liquid at 4°C to a hydrogel at ³ 30°C. The hydrogel, which was designate as ProGel-HMP, allows the sustained retention of the opioid prodrug at sites of pathology. When tested in the destabilization of the medial meniscus (DMM) model of osteoarthritis (OA), ProGel-HMP provided potent and sustained (³ 16 days) pain relief without spinal cord analgesia. Once locally administration, P-HMP slowly dissolves from ProGel-HMP and is processed subcellularly by phagocytic cells to release HMP for sustained local pain relief. The P-HMP that is not sequestered by cells drains into the circulation and rapidly clears via the kidney, effectively limiting systemic exposure. Importantly, the absence of spinal cord analgesia, indicates that the thermoresponsive P-HMP does not permeate the blood-brain or spinal cord barriers, which circumvents the risks of eliciting centrally mediated drug-dependency and addiction associated with conventional opioids. Based on these preliminary findings, we hypothesize that (1) that ProGel-HMP can provide sustained and effective local post-operative analgesia and pain amelioration at sites of musculoskeletal trauma, independent of CNS-mediated effects; (2) that the formulation parameters of ProGel-HMP can be modified to regulate the duration and efficacy of local analgesia to meet the specific needs for pain management in different musculoskeletal conditions. To test these hypotheses, we propose to first establish the dimensions within which the ProGel-HMP formulation parameters can be adjusted to regulate the duration and efficacy of local analgesia (Aim 1). Three pain-causing conditions will then be simulated in mice to allow in vivo assessment of ProGel-HMP. The DMM mice will be used to identify optimal ProGel-HMP formulations for both short-term amelioration of post-operative pain and sustained amelioration of chronic OA pain. In addition to testing efficacy and safety, pharmacokinetics/biodistribution (PK/BD) and functional physiological studies will be performed to dissect ProGel-HMP’s mechanism of action (Aim 2). The final studies will employ a murine closed fracture model to screen for an optimal ProGel-HMP formulation that provides medium-term pain relief in skeletal trauma through the stages of tissue inflammation and early skeletal repair. Efficacy, safety and mechanistic studies that are similar to those in Aim 2 will be performed (Aim 3). At the successful completion of this proposal, we will amass robust evidence supporting our central hypotheses that will ultimately lead to the successful translation of ProGel-HMP into clinical practice.

抽象的肌肉骨骼疾病是急性和慢性疼痛的最常见原因之一。治疗这些疾病的阿片类药物对当前阿片类药物的流行做出了重大贡献。迫切需要开发与阿片类药物一样有效但避免副作用的强效镇痛药，包括为了应对这一挑战，我们开发了一种大分子前药。基于N-(2-羟丙基)甲基丙烯酰胺(HPMA)共聚物的氢吗啡酮(HMP)的(P-HMP)。 HMP含量增加至16wt%，P-HMP的水溶液变得具有热响应性并发生转变从 4°C 的液体到 30°C 的水凝胶该水凝胶被指定为 ProGel-HMP，可以实现当在内侧不稳定中进行测试时，阿片类药物前体在病理部位持续保留。骨关节炎 (OA) 的半月板 (DMM) 模型，ProGel-HMP 提供有效且持续（³ 16 天）的疼痛缓解局部给药后，P-HMP 会慢慢从 ProGel-HMP 中溶解，无需脊髓镇痛。由吞噬细胞进行亚细胞处理，释放 HMP，以持续缓解局部疼痛。未被细胞隔离的物质排入循环系统并通过肾脏迅速清除，有效地限制全身性重要的是，没有脊髓镇痛，表明热反应性 P-HMP 确实有镇痛作用。不渗透血脑或脊髓屏障，从而规避了引发中枢介导的风险根据这些初步发现，我们发现与传统阿片类药物相关的药物依赖性和成瘾性。开发出（1）ProGel-HMP 可以提供持续有效的局部术后镇痛，肌肉骨骼创伤部位的疼痛改善，与中枢神经系统介导的作用无关（2）可以修改ProGel-HMP的配方参数来调节局部镇痛的持续时间和功效以满足不同肌肉骨骼条件下疼痛管理的特定需求来测试这些。假设，我们建议首先建立 ProGel-HMP 配方参数的维度可以调整以调节局部镇痛的持续时间和效果（目标 1）。然后将在小鼠中进行模拟，以便对 ProGel-HMP 进行体内评估。DMM 小鼠将用于识别。最佳 ProGel-HMP 配方，可短期缓解术后疼痛并持续缓解疼痛改善慢性骨关节炎疼痛除了测试功效和安全性外，还测试药代动力学/生物分布。将进行 (PK/BD) 和功能生理学研究来剖析 ProGel-HMP 的作用机制（目标 2）。最终研究将采用小鼠闭合性骨折模型来筛选最佳的 ProGel-HMP。该配方可在骨骼创伤的组织炎症阶段提供中期疼痛缓解以及与目标 2 类似的早期骨骼修复的功效、安全性和机制研究。成功完成该提案后，我们将收集强有力的证据来支持我们的计划。最终将 ProGel-HMP 成功转化为临床实践的中心假设。