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

• 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
• 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

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）导致损伤部位下方的感觉，运动和自主功能的部分或完全丧失。 目前，对SCI没有有效的治疗方法。 这项研究的总体目标是制定有效的治疗策略来减少继发性损伤，并改善SCI后的功能恢复。 许多机制和分子造成了继发损伤。 但是，当前的治疗策略是高度特异性的，仅针对损伤级联中的一个或几个元素，并且在临床试验中基本上没有成功。 Minocycline是SCI的一种高度有希望的治疗干预措施，因为它已被证明针对广泛的二级损伤机制，并通过其抗炎，抗氧化剂和抗凋亡特性来保护神经组织免受SCI后多种神经毒性损伤的保护。 许多研究表明，MH的全身性给药可减少继发性损伤并改善SCI动物模型的功能恢复。 然而，无法翻译实验动物中使用的高剂量（45-90 mg/kg）以耐受剂量（3-6 mg/kg）在人类患者中限制了这种药物在SCI治疗中的临床应用。 此外，MH治疗的持续时间受到限制，因为长期系统地给予高剂量的MH会导致严重的副作用和发病率。 因此，局部药物递送可以潜在地将受伤的脊髓组织暴露于全身给药无法实现的高浓度的MH，同时避免与全身暴露有关的有害副作用。 但是，当前的药物输送系统对于局部递送生物活性MH并不理想，因为MH是一个小分子，具有高水溶性，在水溶液中不稳定。 基于在PI实验室发现的新药物输送机制，具有高药物负荷效率的新型MH颗粒，用于局部递送高剂量的生物活性MH，长时间。 此外，可注射水凝胶用于颗粒封装和局部给药。 可以将颗粒的水凝胶注入受伤部位的受伤脊髓鞘内空间中，以便在损伤部位输送局部药物。 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。 药物输送系统由生物相容性，可生物降解的多糖制成，可确保临床应用的安全性。 初步数据表明，释放米诺环素保留了神经保护作用和抗炎活性。 在这项研究中，我们的目的是1）开发具有体内释放曲线的药物输送系统，该系统与继发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的功效，以减少继发性损伤并改善大鼠挫伤SCI模型的功能恢复。 这些目标的成功完成将促进MH治疗在脊髓损伤中的未来临床应用，以及MH表现出显着的治疗潜力的其他各种使人衰弱的神经系统疾病和损伤。