Local delivery of minocycline to promote neuroprotection and recovery after SCI

局部注射米诺环素以促进 SCI 后的神经保护和恢复

基本信息

批准号：
8571622
负责人：
Yinghui Zhong
金额：
$ 22.96万
依托单位：
DREXEL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-06-15 至 2015-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8571622
关键词：
Adverse effects Animal Model Animals Anti-Inflammatory Agents Anti-inflammatory Antibiotics Antioxidants Apoptosis Apoptotic Axon Biocompatible Caring Cell Death Cerebrospinal Fluid Chronic Clinical Trials Contusions Data Dextran Sulfate Dose Drug Delivery Systems Drug Formulations Ensure Environment Exhibits Future Gel Goals High Pressure Liquid Chromatography Human Hydrogels Indium Inflammation Inflammatory Inflammatory Response Injectable Injury Intrathecal Space Laboratories Lesion Locomotor Recovery Measures Medical Minocycline Modeling Morbidity - disease rate Motor Nervous System Trauma Neurons Oligodendroglia Patients Pharmaceutical Preparations Polymers Polysaccharides Process Property Pump Rattus Recovery Recovery of Function Research Safety Secondary to Sensory Site Solutions Spinal Cord Spinal cord injury System Therapeutic Therapeutic Intervention Time Tissues Translating Trauma Wallerian Degeneration aqueous base clinical application disability effective therapy functional loss gray matter high standard improved in vivo local drug delivery nanoparticle nervous system disorder neuron apoptosis neuroprotection neurotoxic novel particle public health relevance relating to nervous system small molecule submicron treatment effect treatment strategy water solubility white matter

项目摘要

DESCRIPTION (provided by applicant): Traumatic spinal cord injury (SCI) causes partial or complete loss of sensory, motor, and autonomic functions below the injury site. Currently, there are no effective treatments for SCI. The overall goal of this study is to develop an effective therapeutic strategy to reduce secondary injury, and improve functional recovery after SCI. Many mechanisms and molecules contribute to secondary injury. However, current treatment strategies are highly specific, targeting only one or a few elements in the injury cascades, and have been largely unsuccessful in clinical trials. Minocycline is a highly promising therapeutic intervention for SCI because it has been shown to target a broad range of secondary injury mechanisms, and protect neural tissue from multiple neurotoxic insults after SCI, via its anti-inflammatory, anti-oxidant, and anti-apoptotic properties. A number of studies have shown that systemic administration of MH reduces secondary injury and improves functional recovery in various animal models of SCI. However, the inability to translate the high doses (45-90 mg/kg) of MH used in experimental animals to tolerable doses (3-6 mg/kg) in human patients limits the clinical application of this medication for SCI treatment. In addition, the duration of MH treatment is limited because long term systemic administration of high doses of MH has been shown to cause serious side effects and morbidity. Thus local drug delivery can potentially expose the injured spinal cord tissue to high concentrations of MH that systemic administration cannot achieve, while avoiding the deleterious side effects associated with systemic exposure. However, current drug delivery systems are not ideal for local delivery of bioactive MH with sufficient dose and duration because MH is a small molecule with high water solubility and unstable in aqueous solution. Based on a new drug delivery mechanism discovered in the PI's laboratory, novel MH-containing particles with high drug loading efficiency were developed for local delivery of high dose, bioactive MH for an extended period of time. Further, injectable hydrogels were used for particle encapsulation and local administration. The particle-loaded hydrogels can be injected into the intrathecal space of the injured spinal cord for local drug delivery at the injury site. The dose and duration of MH release can be controlled by initial loading and gel formulation. The drug delivery system is made from biocompatible, biodegradable polysaccharides ensuring the safety of clinical applications. Preliminary data shows that released minocycline retained neuroprotective and anti-inflammatory activities. In this study, we aim to 1) develop a drug delivery system with an in vivo release profile that matches the progression of secondary injury for optimum treatment effect; and 2) evaluate the efficacy of this drug delivery system to reduce secondary injury and improve functional recovery in a rat contusion SCI model. Successful completion of these Aims will facilitate future clinical application of MH treatment in spinal cord injury, as well as a variety of other debilitating neurological disorders and injuries where MH has demonstrated remarkable therapeutic potential.

描述（由申请人提供）：创伤性脊髓损伤（SCI）导致损伤部位以下的感觉、运动和自主功能部分或完全丧失。目前，SCI 尚无有效治疗方法。本研究的总体目标是制定有效的治疗策略，以减少继发性损伤，并改善 SCI 后的功能恢复。许多机制和分子都会导致继发性损伤。然而，目前的治疗策略非常具体，仅针对损伤级联中的一个或几个要素，并且在临床试验中基本上不成功。米诺环素是一种非常有前途的 SCI 治疗干预措施，因为它已被证明可以针对广泛的继发性损伤机制，并通过其抗炎、抗氧化和抗凋亡特性保护神经组织免受 SCI 后的多种神经毒性损伤。多项研究表明，全身给予 MH 可减少各种 SCI 动物模型的继发性损伤并改善功能恢复。然而，无法将实验动物中使用的高剂量（45-90 mg/kg）MH转化为人类患者的耐受剂量（3-6 mg/kg）限制了该药物治疗SCI的临床应用。此外，MH 治疗的持续时间是有限的，因为长期全身施用高剂量的 MH 已被证明会导致严重的副作用和发病率。因此，局部药物输送可能会将受损的脊髓组织暴露于全身给药无法达到的高浓度 MH，同时避免与全身暴露相关的有害副作用。然而，由于MH是一种小分子，具有高水溶性并且在水溶液中不稳定，目前的药物递送系统对于以足够的剂量和持续时间局部递送生物活性MH并不理想。基于 PI 实验室发现的新药物递送机制，开发了具有高载药效率的新型含 MH 颗粒，用于长时间局部递送高剂量、生物活性 MH。此外，可注射水凝胶用于颗粒封装和局部给药。负载颗粒的水凝胶可以注射到受伤脊髓的鞘内空间，以在损伤部位进行局部药物输送。 MH 释放的剂量和持续时间可以通过初始加载和凝胶配方来控制。该药物输送系统由生物相容性、可生物降解的多糖制成，确保临床应用的安全性。初步数据显示，释放的米诺环素保留了神经保护和抗炎活性。在这项研究中，我们的目标是：1）开发一种药物递送系统，其体内释放曲线与继发性损伤的进展相匹配，以获得最佳治疗效果； 2) 评估该药物输送系统在大鼠挫伤 SCI 模型中减少继发性损伤和改善功能恢复的功效。这些目标的成功完成将促进未来 MH 治疗在脊髓损伤以及各种其他使人衰弱的神经系统疾病和损伤中的临床应用，在这些疾病和损伤中 MH 已显示出显着的治疗潜力。