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

 描述（由申请人提供）：目前对慢性疼痛的治疗往往不足，需要长期应用，并可能导致依赖和成瘾。特别地，迫切需要用于与炎症相关的神经性疼痛的位点特异性非阿片样物质治疗。该项目首次将治疗诊断纳米医学引入疼痛治疗，旨在减少或消除损伤后对阿片类镇痛的需求。 我们的长期目标是应用新的纳米技术（治疗诊断学），通过减少疼痛和限制药物寻求行为和成瘾来帮助改善患者的治疗效果。尽管已被公认为NSAIDS，但考克斯-2抑制剂受到对神经性疼痛的不良疗效的限制，这可能是由于生物利用度差和无法以足够的剂量到达受损神经。此外，在我们对考克斯-2抑制剂在神经性疼痛中的位点特异性作用的理解以及我们将抑制剂导向损伤位点的能力方面存在重大差距。具体来说，我们的目标是确定针对损伤浸润活化巨噬细胞的纳米颗粒递送的环氧合酶-2（考克斯- 2）抑制剂将导致损伤后疼痛和对阿片类药物治疗的需求减少的程度。 该提案直接涉及C.E.B.R.A.的两个关键标准。程序：1）我们正在测试一个全新的假设，通过测试是否减少神经损伤部位的损伤后浸润巨噬细胞的激活将减少动物的疼痛样行为。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颗粒药物输送疼痛研究。具体来说，我们将应用治疗诊断（治疗和诊断）策略，同时成像和治疗疼痛诱导炎症，并监测活体动物的治疗后变化。在这项提案中，我们的目的是研究巨噬细胞靶向治疗诊断纳米颗粒对慢性压迫性损伤（CCI）动物自发性疼痛和阿片类药物使用的影响。基于这些结果和我们在疼痛生物学和药物科学方面的联合专业知识，我们提出了以下假设：用治疗诊断纳米颗粒抑制浸润巨噬细胞中的考克斯-2将减少CCI大鼠的疼痛样行为和对阿片类镇痛的需求。具体目标1：合成新的治疗诊断纳米颗粒，用于巨噬细胞靶向抗炎作用，并在体外测试其药理学作用。具体目标二：确定巨噬细胞靶向治疗诊断纳米颗粒在神经性疼痛动物模型中显示疗效的程度，并减少对阿片类镇痛的需求。 如果成功，拟议的项目将：1）引入治疗诊断学作为研究动物模型疼痛的新策略; 2）导致新的治疗干预措施，其中巨噬细胞靶向药物递送增加已知抗炎药物治疗神经性疼痛的疗效，从而减少阿片类药物在损伤后镇痛中的使用。

 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.