Nonaddictive opioid prodrug nanomedicine for musculoskeletal pain

摘要 肌肉骨骼疾病是急性和慢性疼痛的最常见原因之一。广泛使用 阿片类药物对这些疾病的治疗对目前阿片类药物的流行做出了重大贡献。有一个 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 依赖和成瘾的风险。为了应对这一挑战，我们开发了一种大分子前药， 在一个实施方案中，本发明涉及基于N-（2-羟丙基）甲基丙烯酰胺（HPMA）共聚物的氢吗啡酮（HMP）（P-HMP）。当 HMP含量增加到16wt%时，P-HMP水溶液具有温敏性， 从4°C的液体到30°C的水凝胶。该水凝胶被命名为ProGel-HMP， 阿片样物质前药在病理部位的持续保留。当在内侧的不稳定中进行测试时， 在骨关节炎（OA）半月板（DMM）模型中，ProGel-HMP提供了有效和持续（≥ 16天）的疼痛缓解 没有脊髓镇痛。一旦局部给药，P-HMP从ProGel-HMP中缓慢溶解， 通过吞噬细胞的亚细胞加工释放HMP，用于持续的局部疼痛缓解。P-HMP是 未被细胞隔离的药物流入循环，并通过肾脏迅速清除，有效地限制了全身性 exposure.重要的是，脊髓镇痛的缺乏表明，温度响应性P-HMP确实 不渗透血脑或脊髓屏障，从而避免了引起中枢介导的 与常规阿片类药物相关的药物依赖和成瘾。根据这些初步调查结果，我们 假设（1）ProGel-HMP可提供持续和有效局部术后镇痛， 肌肉骨骼创伤部位的疼痛改善，独立于CNS介导的作用;（2） 可以修改ProGel-HMP的制剂参数以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。测试这些 假设，我们建议首先建立尺寸，其中ProGel-HMP配方参数 可以调整以调节局部镇痛的持续时间和疗效（目的1）。三种引起疼痛的情况 然后在小鼠中模拟，以允许体内评估ProGel-HMP。DMM小鼠将用于识别 最佳的ProGel-HMP制剂，用于短期改善术后疼痛和持续 改善慢性OA疼痛。除了测试有效性和安全性外，药代动力学/生物分布 (PK/BD）和功能生理学研究，以剖析ProGel-HMP的作用机制 (Aim 2）。最后的研究将采用小鼠闭合性骨折模型来筛选最佳的ProGel-HMP 通过组织炎症阶段提供骨骼创伤中期疼痛缓解的制剂 和早期骨骼修复与目标2相似的有效性、安全性和机制研究将在 （目标3）。在成功完成这一提案后，我们将收集强有力的证据， 中心假设，最终将导致ProGel-HMP成功转化为临床实践。

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.