Nonaddictive opioid prodrug nanomedicine for musculoskeletal pain

摘要 肌肉骨骼疾病是引起急性和慢性疼痛的最常见原因之一。广泛使用 这些条件下的阿片类药物的使用对目前的阿片类药物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止痛药，包括 依赖和上瘾的风险。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)(P-HMP)。什么时候 HMP的含量增加到16wt%，P-HMP的水溶液变得热响应和转变 从4°C的液体到30°C的水凝胶，这种水凝胶被指定为ProGel-HMP，允许 阿片前药在病理部位的持续滞留。在内侧不稳定的情况下进行测试时 半月板(DMM)模型的骨关节炎(OA)，ProGel-HMP提供了有效和持续的疼痛缓解(16天 没有脊髓止痛。一旦局部给药，P-HMP就会慢慢从ProGel-HMP中溶解，并 经吞噬细胞亚细胞处理后释放HMP，可持续缓解局部疼痛。P-HMP，即 没有被细胞隔离的物质流入循环，并通过肾脏迅速清除，有效地限制了全身 曝光。重要的是，没有脊髓止痛，表明温度响应性P-HMP起作用 不会渗透到血脑或脊髓屏障，从而规避了集中诱导的风险 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可提供持续有效的术后局部镇痛和 肌肉骨骼创伤部位的疼痛改善，不受中枢神经系统介导的影响；(2) ProGel-HMP的处方参数可被修改以调节局部镇痛的持续时间和疗效 以满足不同肌肉骨骼条件下疼痛管理的特定需求。为了测试这些 假设，我们建议首先建立ProGel-HMP配方参数的维度 可调整以调节局部止痛的持续时间和疗效(目标1)。三种引起疼痛的情况 然后在小鼠身上模拟，以便在体内评估ProGel-HMP。DMM小鼠将被用来识别 既能短期缓解术后疼痛又能持续的最佳ProGel-HMP制剂 改善慢性骨性关节炎疼痛。除了测试有效性和安全性外，药代动力学/生物分布 将进行(PK/BD)和功能生理学研究以剖析ProGel-HMP的作用机制 (目标2)。最后的研究将使用小鼠闭合性骨折模型来筛选最佳的ProGel-HMP 通过组织炎症阶段为骨骼创伤提供中期止痛的制剂 和早期骨骼修复。与目标2类似的有效性、安全性和机制研究将是 已执行(目标3)。在成功完成这项提议后，我们将收集有力的证据来支持我们的 最终将导致ProGel-HMP成功转化为临床实践的中心假设。

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.