Targeting Nanotherapeutics for Neuroprotection after Acute Spinal Cord Injury

脊髓损伤(Sci)是一种严重的医学问题，可导致感觉、运动和自主神经丧失。 由于中枢神经细胞的损伤而发挥作用。到目前为止，还没有针对脊髓损伤的完全恢复性疗法，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 在急性损伤后的功能，因为其高的脂质过氧化抑制和抗炎的效力。 然而，这种药物的使用仍然存在争议，因为它对神经细胞的适度保护功能是 被身体其他部位的不良副作用所掩盖。 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- 共轭MP(Nano-MP)，由MP和载体(N，2-羟丙基甲基丙烯酰胺)组成。我们的 令人兴奋的初步数据表明，通过一次给药，纳米MP能够优先 在脊髓损伤的啮齿动物模型中，药物被隔离在受损的脊髓部位，并 主要由浸润性炎症细胞(从母体MP分子的作用推断)保留 好几天了。与传统的静脉注射MP分子相比，单次剂量的纳米- MP可显著抑制损伤脊髓的氧化应激反应。此外，我们还建立了 类似的地塞米松纳米粒作为抗炎剂，具有更高的疗效和 减少佐剂性关节炎和狼疮性肾炎的副作用。 根据这一证据，我们假设靶向MP输送到损伤部位具有类似的或 卓越的治疗效果(例如，由于更高的输送效率，该方法将与 在减少副作用的同时减少脂质过氧化、炎症和神经损伤)治疗急性脊髓损伤 效果(例如，对肌肉、骨骼不利的那些)，与传统的静脉给药相比 母体MP分子。在这个R21项目中，我们提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效果， 急性脊髓损伤后的氧化应激、炎症、神经损伤和伤口愈合(目标1)。我们将进一步 评估与游离MP相比，纳米MP给药是否减少了对 急性脊髓损伤后骨骼肌和骨骼(目标2)。 这类项目的成功完成预计将提供一个基于证据的理由 进一步评价纳米微球对急性脊髓损伤后功能恢复的影响 临床研究，以测试这一创新治疗的疗效。如果在进一步的研究中被证明是有效的， 管理纳米技术使MP有潜力成为一个实用的和真正令人兴奋的专业 急性脊髓损伤后个体功能保护的研究进展。这一系列研究的完成将导致 安全、方便、有效和负担得起的靶向治疗，以提供神经保护和改善 急性脊髓损伤患者的功能恢复。

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.