Targeting Nanotherapeutics for Neuroprotection after Acute Spinal Cord Injury

脊髓损伤（Spinal cord injury，SCI）是一种严重的医学问题，可导致感觉、运动和自主神经功能的丧失 由于中枢神经细胞的损伤。到目前为止，还没有完全恢复SCI的治疗方法，但 有一种FDA批准的药物甲基强的松龙（MP）正在临床上用于改善 由于它们的高脂质过氧化抑制和抗炎效力，在急性损伤后发挥作用。 然而，这种药物的使用仍然存在争议，因为对神经细胞的适度保护功能是 对身体其他部分的不利副作用所掩盖。 为了提高疗效和减少副作用，我们设计并合成了一种纳米颗粒- 偶联MP（Nano-MP），其由MP和载体（N2-羟丙基甲基丙烯酰胺）组成。我们 令人兴奋的初步数据表明，纳米MP，通过单次给药，能够优先 递送到SCI啮齿动物模型中的脊髓损伤部位，在那里药物被隔离， 主要由浸润的炎性细胞保留（从母体MP分子的作用推断）， 几天与MP分子的常规静脉内递送相比，单剂量的Nano- MP管理显着抑制氧化应激损伤脊髓。此外，我们还建立了 地塞米松作为抗炎剂的类似纳米颗粒递送具有增加的功效， 减少了药物引起的关节炎和狼疮性肾炎的副作用。 基于这一证据，我们假设MP靶向输送至损伤部位具有类似或 上级治疗功效（例如，由于更高的交付效率，这种方法将与 减少脂质过氧化、炎症和神经损伤），同时减少副作用。 效果（例如，对肌肉、骨骼有不利影响的那些）。 亲本MP分子。在这个R21项目中，我们提出了一系列临床前实验来测试我们的 假设我们将首先确定Nano-MP对脂质过氧化的潜在治疗效果， 急性SCI后的氧化应激、炎症、神经损伤和伤口愈合（目的1）。我们将进一步 评价与游离MP相比，Nano-MP给药是否导致对以下方面的不良反应减少： 急性脊髓损伤后骨骼肌和骨（Aim 2）。 这类项目的成功完成将提供一个基于证据的理由， 进一步评估Nano-MP对急性SCI后功能恢复的影响，并强烈支持早期 临床研究，以测试这种创新疗法的疗效。如果在进一步的研究中证明它有效， 纳米技术使MP的管理有可能成为一个实际的，真正令人兴奋的主要 在急性脊髓损伤后保护功能。这一系列研究的完成将导致 安全，方便，有效，负担得起的靶向治疗，以提供神经保护和改善 急性SCI患者的功能恢复。

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.