Targeting Nanotherapeutics for Neuroprotection after Acute Spinal Cord Injury

靶向纳米疗法对急性脊髓损伤后的神经保护

• 批准号: 9891695
• 负责人: Weiping Qin
• 金额: $ 35.94万
• 依托单位: BRONX VETERANS MEDICAL RESEARCH FDN
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-01 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9891695
• 关键词: Acute; Address; Adjuvant Arthritis; Adverse effects; Affect; Animals; Anti-Inflammatory Agents; Apoptotic; Blood; Bone Density; Caring; Cells; Clinical; Clinical Investigator; Clinical Management; Clinical Research; Collaborations; Complex; Data; Deterioration; Development; Dexamethasone; Direct Costs; Dose; Drug usage; Event; FDA approved; Facilities and Administrative Costs; Female; Gastrointestinal Hemorrhage; Health Care Costs; Hemorrhagic Disorders; Impairment; Individual; Infection; Inflammation; Inflammatory Infiltrate; Injury; Intervention; Intravenous; Lead; Legal patent; Lesion; Life; Lipid Peroxidation; Lupus Nephritis; Medical; Medical center; Medicine; Methylprednisolone; Modeling; Motor; Muscle; Muscular Atrophy; Myopathy; Nanotechnology; Nebraska; Neurologic; Neurologic Deficit; Neurons; Neuropathy; Neurosciences; Operative Surgical Procedures; Oxidative Stress; Parents; Patients; Persons; Pharmaceutical Preparations; Procedures; Protocols documentation; Public Health; Rattus; Recovery of Function; Research; Rest; Risk; Rodent Model; Route; Seasons; Sensory; Series; Severities; Site; Skeletal Muscle; Skeletal bone; Spinal Cord; Spinal Cord Contusions; Spinal cord injury; Steroids; Structure; Tail; Testing; Time; Tissues; Treatment Efficacy; United States; Universities; Veins; base; bone; bone loss; carbohydrate metabolism; design; disability; dosage; efficacy testing; evidence base; experience; experimental study; functional improvement; improved; improved functioning; innovation; interest; intravenous administration; male; methacrylamide; multidisciplinary; muscle form; nano; nanomaterials; nanomedicine; nanoparticle; nanoparticle delivery; nanotherapeutic; neuroprotection; novel; novel drug class; novel therapeutics; pre-clinical; preservation; prevent; relating to nervous system; side effect; skeletal; socioeconomics; targeted delivery; targeted treatment; therapeutic effectiveness; therapy design; translational scientist; wound healing

Spinal cord injury (SCI) is a serious medical problem that causes loss of sensory, motor and autonomic function due to the damage of central nerve cells. There are no fully restorative therapies for SCI so far, but there is one FDA approved agent methylprednisolone (MP) that is being used clinically for the improvement of function after acute injury because of their high lipid peroxidation inhibition and anti-inflammatory potency. However, the use of this drug remains controversial as the modest protective functions on nerve cells are overshadowed by the unfavorable side effects to the rest of the body. To increase efficacy and reduce their side effects, we have designed and synthesized a nanoparticles- conjugated MP (Nano-MP), which is composed of MP and a carrier (N2-hydroxypropyl methacrylamide). Our exciting preliminary data demonstrated that the Nano-MP, by a single administration, is able to be preferentially delivered to the site of the injured spinal cord in a rodent model of SCI, where the drug is sequestered and retained mainly by infiltrating inflammatory cells (extrapolated from the action of the parent MP molecule) for several days. Compared to conventional intravenous delivery of the MP molecule, the single dose of the Nano- MP administration significantly inhibited oxidative stress in the injured spinal cord. Additionally, we established a similar nanoparticle delivery of dexamethasone as an anti-inflammatory agent with increased efficacy and reduced side effects in adjuvant-induced arthritis and lupus nephritis. Based on this evidence, we hypothesize that the targeted MP delivery to the injury site has similar or superior therapeutic efficacy (e.g., because of greater delivery efficiency, this approach will be associated with reduced lipid peroxidation, inflammation and neural damage) in the treatment of acute SCI while reducing side effects (e.g., those adversely affecting muscle, bone), compared to conventional intravenous delivery of the parent MP molecule. In this R21 project, we propose to a series of preclinical experiments to test our hypotheses. We will first determine the potential therapeutic efficacy of Nano-MP on lipid peroxidation, oxidative stress, inflammation, neural damage and wound-healing after acute SCI (Aim 1). We will further evaluate if Nano-MP administration, compared to that of free MP, results in a reduction in adverse effects on skeletal muscle and bone after acute SCI (Aim 2). The successful completion of the projects of this kind is expected to provide an evidence-based rationale to further evaluate the effects of Nano-MP on functional recovery after acute SCI, and to strongly support early clinical studies to test the efficacy of this innovative treatment. If it proven to efficacious in further studies, administration of nanotechnology-enabled MP holds the potential to be a practical and truly exciting major advance to preserve function in individuals after acute SCI. The completion of this line of research will lead to a safe, convenient, effective, and affordable targeted-therapy to provide neuroprotection and to improve functional recovery for persons with acute SCI.

脊髓损伤（SCI）是一个严重的医疗问题，会导致感觉，运动和自主神经损失 由于中央神经细胞的损害而引起的功能。到目前为止，还没有SCI的完全恢复性疗法，但是 有一个FDA批准的药剂甲基丙酮（MP）正在临床上用于改进 由于其高脂质过氧化抑制和抗炎效力，急性损伤后的功能。 但是，由于神经细胞上适度的保护功能是 对身体其余部分的不利副作用所掩盖。 为了提高功效并降低其副作用，我们设计和合成了纳米颗粒 - 共轭MP（纳米MP），由MP和载体组成（N2-羟基丙烯酰胺）。我们的 令人兴奋的初步数据表明，单个管理的纳米MP能够优先 在SCI的啮齿动物模型中，递送到受伤的脊髓的部位，该药物被隔离并 主要通过浸润炎性细胞（从母体MP分子的作用外推）保留 几天。与MP分子的常规静脉输送相比，纳米的单剂量 MP给药可显着抑制受伤的脊髓中的氧化应激。此外，我们建立了 地塞米松的类似纳米颗粒作为一种抗炎剂，具有增加的功效和 佐剂引起的关节炎和狼疮肾炎的副作用减少。 基于此证据，我们假设有针对性的MP向伤害部位交付具有相似或 出色的治疗功效（例如，由于交付效率的提高，这种方法将与 急性SCI治疗时，脂质过氧化，炎症和神经损伤减少了 与常规的静脉注射递送相比 母体MP分子。在这个R21项目中，我们建议进行一系列临床前实验，以测试我们的 假设。我们将首先确定纳米MP对脂质过氧化的潜在治疗功效， 急性SCI后氧化应激，炎症，神经损伤和伤口愈合（AIM 1）。我们将进一步 评估纳米MP是否与游离MP相比，会导致对 急性SCI后骨骼肌和骨骼（AIM 2）。 预计此类项目的成功完成将提供基于证据的理由 进一步评估纳米MP对急性SCI后功能恢复的影响，并早期强烈支持 临床研究以测试这种创新治疗的功效。如果证明在进一步的研究中有效， 纳米技术的管理MP具有成为实用而真正令人兴奋的专业的潜力 急性科学后的个体保持功能。这一研究的完成将导致 安全，方便，有效且负担得起的靶向治疗可提供神经保护并改善 急性科幻患者的功能恢复。