Systemic Application for Injury Site Specific Delivery via Neutrophils to Treat B

通过中性粒细胞进行损伤部位特异性递送来治疗 B 的系统应用

• 批准号: 9527023
• 负责人: XUDONG J. LI
• 金额: $ 26.86万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-19 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9527023
• 关键词: Acute; Adverse effects; Air Embolism; American; Animal Experimentation; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Antibodies; Antiinflammatory Effect; Appointment; Area; Back; Back Pain; Binding; Biological; Chemistry; Chronic; Clinic; Clinical; Clinical Trials; Common Cold; Development; Ensure; Enzyme Inhibitor Drugs; Epidural Injections; Equipment; Ethers; Event; Fluoroscopy; Fullerenes; Half-Life; Health; Hematoma; Hernia; Hydrophobicity; Hyperalgesia; Image; In Vitro; Infection; Infiltration; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Injections; Injury; Intervertebral disc structure; Knock-out; Knockout Mice; Link; Low Back Pain; Measurement; Methods; Modeling; Modification; Mus; Nanoconjugate; Neck; Needles; Nerve; Nurses; Operative Surgical Procedures; Pain; Pain in lower limb; Parents; Patients; Peptides; Peripheral; Pharmaceutical Preparations; Plant Roots; Polyethylene Glycols; Property; Proteins; Proteolysis; Publishing; Puncture procedure; Radiculopathy; Research; Research Personnel; Resistance; Resolution; Risk; Roentgen Rays; Role; Signal Transduction; Site; Slipped Disk; Spinal Ganglia; Steroids; Surgeon; Suspensions; System; TNF gene; Technical Expertise; Testing; Therapeutic Agents; Tissues; Training; Translational Research; Treatment Efficacy; Validation; Vasovagal Syncope; Veins; Vertebral column; Work; aqueous; base; biomaterial compatibility; chronic back pain; compare effectiveness; cost effective; cost effectiveness; disability; effective therapy; fMet-Leu-Phe receptor; flu; imaging agent; imaging probe; in vivo; insight; intervertebral disk degeneration; macrophage; molecular imaging; mouse model; nano; nanostructured; neutrophil; novel; novel strategies; nucleus pulposus; outcome prediction; pain relief; public health relevance; receptor; receptor expression; single photon emission computed tomography; small molecule; synthetic peptide

DESCRIPTION (provided by applicant): Low back pain is an endemic problem and is the second most common reason that Americans go to see their doctor, second only to the most common cold and the flu. Low back pain is also the second most common illness-related reason given for a missed workday and the most common cause of disability. In recent years, a body of research has suggested a possible role of injury-induced inflammation in low back pain caused by damaged and degenerating intervertebral discs. As such, the use of fluoroscopy-guided lumbar epidural injections of steroids to reduce the local chemo-inflammatory response has increased dramatically since their inception as a treatment in the 1950s. However, the risks of epidural injections include, but are not limited to, epidural hematoma, epidural infection, nerve root injury, dural puncture, air embolism and vasovagal syncope. Moreover, the epidural injection is technically demanding. It is usually performed under x-ray by doctors with special training. When a patient gets an appointment, the pain is likely in a more subacute or chronic state. Therefore, a cost-effective treatment for acute/chronic back pain is of great importance. Our application proposes a novel treatment by linking nano-fullerene to cFLFLF in order to specifically target activated neutrophils that migrate into the disc herniation site and treat acut back pain via peripheral vein injection, which is not technically demanding and could be performed by a nurse. Nano-fullerene, which has potent anti-oxidative and anti-inflammatory properties, without specific biological target could not only reduce hyperalgesia induced by the extrusion of nucleus pulposus tissue from herniated discs, but also eliminate the side effects associated with standard biological target-oriented drug molecules. However, an effective delivery system is needed to overcome its highly hydrophobic properties to specifically target the site of injury. The overall hypothesis of this study is that the activated neutrophils expressig formyl peptide receptor (FPR) will bind to proteolytically resistant synthetic peptide cFLFLF and that together they will infiltrate and accumulate into the site of inflammation in the herniated dic. Linking nano-fullerene to a cFLFLF (cFLFLF-PEG-fullerene) will ensure event-specific temporal and spatial delivery of the anti-inflammatory agent to the site of injury via systemic injection to treat the pain caused by excessive inflammation in and around herniated discs. In Aim 1 of the proposed study, we will characterize the infiltration of activated neutrophils into an acute disc herniation using neutrophil-specific small molecule imaging agents and immunohistology. The imaging signal will be validated using FPR knockout mice. The neutrophils and macrophages will be analyzed for expression and quantification of FPR and for the quantification of injury. In Aim 2, we will characterize the inhibitory effect of aqueous suspensions of nano-fullerene on local inflammation induced by disc herniation in vitro and in vivo. In Aim 3, we will synthesize cFLFLF-PEG-fullerene and evaluate its systemic vs. local delivery to a site of inflammation in a mouse radiculopathy model; we will also assess injury site target systemic delivery vs. non- specific systemic delivery using wild type and FPR knockout mice in a disc degeneration model induced by needle puncture. This study will provide useful insights into a novel cost-effective therapeutic strategy for acute and chronic back/neck/leg pain involving systemic injection of non-protein, nano-structured, biocompatible fullerene conjugated with cFLFLF, a neutrophil-specific binding peptide. This method is much more cost- effectiveness compared to epidural steroid injection.

描述(申请人提供)：腰痛是一种地方性问题，也是美国人去看医生的第二大常见原因，仅次于最常见的感冒和流感。腰痛也是错过工作日的第二大与疾病有关的原因，也是导致残疾的最常见原因。近年来，大量研究表明，损伤引起的炎症在腰椎间盘受损和退变引起的下腰痛中可能起到了作用。因此，自从20世纪50年代作为一种治疗方法开始以来，使用透视引导的腰椎硬膜外类固醇注射来减少局部化学性炎症反应的使用已经显著增加。然而，硬膜外注射的风险包括但不限于硬膜外血肿、硬膜外感染、神经根损伤、硬膜穿刺术、空气栓塞和血管迷走性晕厥。此外，硬膜外注射技术要求很高。它通常是由受过特殊训练的医生在X光下进行的。当病人得到预约时，疼痛可能处于亚急性或慢性状态。因此，一种经济有效的治疗急/慢性背痛是非常重要的。我们的申请提出了一种新的治疗方法，将纳米富勒烯连接到cFLFLF上，以便专门针对迁移到椎间盘突出部位的激活的中性粒细胞，并通过外周静脉注射治疗急性背痛，这在技术上不是很苛刻的，可以由护士进行。纳米富勒烯具有很强的抗氧化和抗炎作用，在没有特定生物靶点的情况下，不仅可以减轻髓核组织从突出的椎间盘中挤出所引起的痛觉过敏，而且还可以消除标准生物靶向药物分子的副作用。然而，需要一个有效的递送系统来克服其高度疏水的特性，以特定地靶向损伤部位。本研究的总体假设是，表达甲酰肽受体(FPR)的中性粒细胞将与具有蛋白水解性的合成肽cFLFLF结合，并共同渗透和积聚到腹股沟腹股沟的炎症部位。将纳米富勒烯连接到cFLFLF(cFLFLF-PEG-Fullerene)将确保通过全身注射将抗炎剂在事件特定的时间和空间上输送到损伤部位 治疗因突出的椎间盘及其周围过度炎症而引起的疼痛。在拟议研究的目标1中，我们将使用中性粒细胞特异性小分子显像剂和免疫组织学来表征活化的中性粒细胞在急性腰椎间盘突出症中的渗透情况。成像信号将使用FPR基因敲除小鼠进行验证。将分析中性粒细胞和巨噬细胞的表达和fpr的定量，以及损伤的定量。在目的2中，我们将在体内外研究纳米富勒烯水悬浮剂对腰椎间盘突出症局部炎症的抑制作用。在目标3中，我们将合成cFLFLF-PEG-Fullerene，并在小鼠神经根病模型中评估其全身和局部给药到炎症部位的效果；我们还将在针刺诱导的椎间盘退变模型中使用野生型和FPR基因敲除小鼠评估损伤部位靶向全身给药和非特异性全身给药。这项研究将为治疗急慢性背部/颈部/腿部疼痛的新的具有成本效益的治疗策略提供有用的见解，该策略包括全身注射非蛋白质、纳米结构、生物相容性的富勒烯与中性粒细胞特异性结合多肽cFLFLF。与硬膜外注射类固醇相比，这种方法具有更高的成本效益。

项目成果

Nanoparticle fullerol alleviates radiculopathy via NLRP3 inflammasome and neuropeptides.

• DOI: 10.1016/j.nano.2017.03.015
• 发表时间: 2017-08
• 期刊: Nanomedicine : nanotechnology, biology, and medicine
• 作者: Jin L;Ding M;Oklopcic A;Aghdasi B;Xiao L;Li Z;Jevtovic-Todorovic V;Li X
• 通讯作者: Li X

Detecting Chronic Post-Traumatic Osteomyelitis of Mouse Tibia via an IL-13Rα2 Targeted Metallofullerene Magnetic Resonance Imaging Probe.

• DOI: 10.1021/acs.bioconjchem.6b00708
• 发表时间: 2017-02-15
• 期刊: Bioconjugate chemistry
• 影响因子: 4.7
• 作者: Xiao L;Li T;Ding M;Yang J;Rodríguez-Corrales J;LaConte SM;Nacey N;Weiss DB;Jin L;Dorn HC;Li X
• 通讯作者: Li X