Targeted treatment for radiculopathy via engineered PLA2-responsive multifunctional micelles

摘要 神经根损伤是脊椎损伤、椎管狭窄或椎间盘突出所致神经根病的主要原因，通常 产生一系列复杂的神经病理反应，包括疼痛，这通常会变成慢性的。 许多药理学方法已被用于治疗创伤所致的神经根病，如阿片类药物。 止痛药和非阿片类止痛药。然而，生物利用度，药代动力学，耐受性，广泛 目前常规治疗方法的作用机制和副作用具有很大的风险 毒性和成瘾。此外，缺乏有效性和有限的治疗方法出现了任何强有力的 临床的成功，强调了为痛性神经根病制定更有效的治疗策略的必要性。 神经炎症在神经根创伤后引起疼痛中起着重要作用，并有助于其 在一系列病理中的维持。磷脂酶-A2(PLA2)酶是一种强有力的调节剂。 炎症的发展。我们有证据表明神经根疼痛后脊髓内PLA2升高 在药物输送的PLA2反应平台的建设方面有经验。我们进一步 证明PLA2反应胶束在预防疼痛发作方面实质上有效 老鼠。我们推测，PLA2既可能是局部和脊髓神经炎的独特信号，也可能是 也为治疗神经根病后疼痛提供了一个新的治疗靶点。 根部受伤。这项提议的总体目标是开发一个新的介入平台，以实现更大的 神经根病的治疗效果。为了实现这一目标，我们将开发响应PLA2的 多功能纳米粒子(PRMN)，包括磁共振(MR)造影剂和抗肿瘤药物 炎症和神经调节药物。高分辨率磁共振成像有望提供对 病理状态和药物的定位。PLA2响应属性将允许自 基于损伤和/或疼痛状态诱导的PLA2活性水平的药物释放的调节。 我们将在临床相关的大鼠神经模型上测试PRMNS是否能提供一种治疗疼痛的新策略 牙根创伤。就我们所知，还没有研究试图结合和/或利用这方面的 炎症和PLA2反应，以开发有效的疼痛治疗。我们假设这是 将诊断和治疗功能集成到一个单一系统中的治疗试剂，提供了 临床监测和治疗直肠癌患者的独特机遇和巨大潜力 翻译影响。该提案的具体目标是：1)合成PRMN并对其进行表征 体外实验；2)体外药物释放、抗炎效果及细胞毒性评价；3)体外实验。 评价PRMN治疗神经根损伤后的疼痛和神经炎症 那只老鼠。

ABSTRACT Nerve root trauma is a leading cause of radiculopathy from spinal injury, stenosis, or disc herniation and often produces a complex cascade of neuropathological responses, including pain, which can often become chronic. Many pharmacologic approaches have been pursued to treat trauma-induced radiculopathy, such as opioid analgesics and non-opioid analgesics. However bioavailability, pharmacokinetics, tolerability, broad mechanisms of action and side effects of current conventional treatment approaches carry a substantial risk of toxicity and addiction. In addition, the lack of effectiveness and limited therapies emerging with any robust clinical success, underscore the need to develop more effective treatment strategies for painful radiculopathy. Neuroinflammation has a potent role in initiating pain following nerve root trauma and contributes to its maintenance in a host of pathologies. Phospholipase-A2 (PLA2) enzymes are potent modulators in the development of inflammation. We have evidence of elevated PLA2 in the spinal cord after painful nerve root injury and have experience in the construction of PLA2-responsive platforms for drug delivery. We further demonstrate that the PLA2-responsive micelles are substantially effective in preventing the onset of pain in rats. We hypothesize that PLA2 could both be a unique signature of local and spinal neuroinflammation and also provide a novel therapeutic target for the treatment of pain that develops with radiculopathy after nerve root injury. The overall goal of this proposal is to develop a novel interventional platform for greater effectiveness in radiculopathy treatment. In an attempt to achieve this goal, we will develop PLA2-responsive multifunctional nanoparticles (PRMNs) that incorporate magnetic resonance (MR) contrast agents and anti- inflammatory and neuromodulatory drugs. High resolution MR imaging is expected to provide insight into the pathological state and the localization of the drug. The PLA2-responsive property will allow for the self- modulation of drug release based on the level of PLA2 activity that is induced by the injury and/or pain state. We will test whether PRMNs can provide a novel strategy to treat pain in a clinically relevant rat model of nerve root trauma. To the best of our knowledge, no studies have sought to combine and/or leverage this aspect of the inflammatory and PLA2-response for developing effective pain treatment. We hypothesize that this theranostic agent, which integrates both diagnostic and therapeutic functions into a single system, offers a unique opportunity and tremendous potential for monitoring and treating patients with direct clinically translational impact. The specific aims for the proposal are 1) PRMNs will be synthesized and characterized in vitro; 2) evaluate the drug release, anti-inflammatory effectiveness and cytotoxicity of PRMNs in vitro; and 3) evaluate pain and neuroinflammation after PRMN treatment of nerve root trauma in a well-established model in the rat.