Theranostic Pain Nanomedicines: imaging inflammation, reducing pain and need for opioids

 描述(申请人提供)：目前对慢性疼痛的治疗方法往往不够充分，需要长时间的应用，并可能导致依赖和成瘾。特别是，迫切需要针对炎症相关的神经病理性疼痛进行特定部位的非阿片类药物治疗。拟议的项目首次将鼻腔纳米药物引入疼痛治疗，目的是减少或消除损伤后对阿片类止痛的需求。我们的长期目标是应用新的纳米技术(治疗)，通过减轻疼痛和限制寻求药物的行为和成瘾来帮助改善患者的预后。尽管COX-2抑制剂已被公认为非类固醇类药物，但它对神经病理性疼痛的疗效有限，可能是由于生物利用度低，无法达到足够剂量的受损神经。此外，在我们对COX-2抑制剂在神经病理性疼痛背景下的部位特异性作用的理解以及我们将抑制剂引导到损伤部位的能力方面，存在着重大的差距。具体地说，我们的目标是确定针对损伤的纳米颗粒递送的环氧合酶-2(COX-2)抑制剂渗入激活的巨噬细胞将在多大程度上减少损伤后疼痛和对阿片类药物治疗的需求。这项建议直接解决了C.E.B.R.A.计划的两个关键标准：1)我们正在测试一个全新的假设，即减少损伤后神经损伤部位渗透的巨噬细胞的激活是否会纠正动物的疼痛行为。2)我们正在引入一种全新的技术，通过使用成像支持的靶向纳米药物传递来进行疼痛研究。具体地说，我们将应用治疗(治疗和诊断)策略来同时成像和治疗疼痛诱导的炎症，并监测治疗后活动物的变化。在这项建议中，我们旨在研究巨噬细胞靶向治疗纳米粒对慢性收缩损伤(CCI)动物自发性疼痛和阿片类药物使用的影响。基于这些结果以及我们在疼痛生物学和药学方面的联合专业知识，我们提出了以下假设：用抗痛觉纳米粒抑制COX-2在巨噬细胞中的渗透将减少CCI大鼠的痛样行为和对阿片类止痛的需求。这一假说将通过以下特定目标来验证：特定目标1：合成新的针对巨噬细胞的抗炎作用的抗炎纳米粒，并在体外测试其药理作用。具体目标2：确定巨噬细胞靶向治疗纳米粒在神经病理性疼痛的动物模型中显示效果的程度，并减少对阿片类止痛的需求。拟议的项目如果成功，将：1)引入治疗学作为在动物模型中研究疼痛的新策略；以及2)导致新的治疗干预措施，其中巨噬细胞靶向给药增加已知抗炎药物在治疗神经病理性疼痛方面的疗效，从而减少阿片类药物在损伤后止痛中的使用。

 DESCRIPTION (provided by applicant): Current treatments for chronic pain are often inadequate, require prolonged application, and can lead to dependence and addiction. In particular, there is a pressing need for site-specific non-opioid treatments for neuropathic pain associated with inflammation. The proposed project for the first time introduces theranostic nanomedicine to treatment of pain with aim to reduce or eliminate need for opioid analgesia post-injury. Our long-term goal is to apply novel nanotechnology (theranostics) to help improve patient outcomes by reducing pain and limiting drug-seeking behavior and addiction. Although well established as NSAIDS, COX-2 inhibitors are limited by poor efficacy on neuropathic pain, likely due to poor bioavailability and inability to reach injured nerves in sufficient doses. Furthermore, a major gap exists in our understanding of the site-specific actions of COX-2 inhibitors in the context of neuropathic pain and our ability to direct inhibitors to the site of ijury. Specifically we aim to determine the extent to which a nanoparticle-delivered cyclooxygenase-2 (COX- 2)-inhibitor directed at injury infiltrating activated macrophages will lead to decreases in post-injury pain and need for opioid treatment. This proposal directly addresses two key criteria for the C.E.B.R.A. program: 1) We are testing a completely new hypothesis by testing whether reducing activation of post-injury infiltrating macrophages at the site of a nerve injury will redue pain-like behavior in animals. 2) We are introducing a completely novel technology to pain research by using imaging-supported targeted nanoparticle drug delivery. Specifically, we will apply a theranostic (therapeutic and diagnostic) strategy to simultaneously image and treat pain-inducing inflammation and monitor post-treatment changes in live animals. In this proposal we aim to investigate effects of macrophage targeted theranostic nanoparticles on spontaneous pain and opioid use in chronic constriction injured (CCI) animals. Based on these results and our joint expertise in pain biology and pharmaceutical sciences, we propose the following hypothesis: Inhibition of COX-2 in infiltrating macrophages with theranostic nanoparticles will reduce pain-like behavior and need for opioid analgesia in rats with CCI. This hypothesis will be tested by the following specific aims: Specific Aim 1: Synthesize new theranostic nanoparticles for macrophage-targeted anti-inflammatory action and test their pharmacological effects in vitro. Specific Aim 2: Determine the extent that macrophage targeted theranostic nanoparticles will show efficacy in an animal model of neuropathic pain and reduce need for opioid analgesia. The proposed project, if successful, will: 1) introduce theranostics as novel strategies for studying pain in animal models; and 2) lead to new therapeutic interventions, where macrophage-targeted drug delivery increases efficacy of known anti-inflammatory drugs in treating neuropathic pain leading to reduced use of opioids in post-injury analgesia.