Nanotherapies for the treatment of neurodevelopmental disorders.

用于治疗神经发育障碍的纳米疗法。

• 批准号: 8671529
• 负责人: Kannan Rangaramanujam
• 金额: $ 36.45万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8671529
• 关键词: Acetylcysteine; Adult; Affect; Age; Age-Months; Astrocytes; Autistic Disorder; Birth; Blood - brain barrier anatomy; Blood Circulation; Blood Circulation Time; Brain; Brain Injuries; Cells; Cerebral Palsy; Chemistry; Child; Childhood; Chronic; Clinical; Dendrimers; Development; Diffuse; Disease; Disulfides; Dose; Drug Delivery Systems; Drug Formulations; Drug Kinetics; Economic Burden; Esters; Fluorescence; Generations; Goals; Human; Hydroxyl Radical; Immunohistochemistry; Inflammation; Injury; Life; Ligands; Link; Mannose; Mediating; Microglia; Modeling; Motor; Nanotechnology; Neonatal; Nervous System Physiology; Neurodevelopmental Disorder; Neuronal Injury; Newborn Infant; Organ; Oryctolagus cuniculus; Pathogenesis; Pathology; Perinatal; Pharmaceutical Preparations; Phase; Phenotype; Plasma; Play; Positron-Emission Tomography; Prenatal Injuries; Proteins; Public Health; Research; Role; Safety; Surface; Technology; Testing; Therapeutic; Toxic effect; Translations; attenuation; base; cyanine dye 5; design; disability; improved; in vivo; innovation; interest; intravenous administration; mannose receptor; motor function improvement; myelination; nanoparticle; nanotherapeutic; nanotherapy; nervous system disorder; neuroinflammation; novel; novel therapeutic intervention; overexpression; postnatal; prenatal; public health relevance; receptor; social; uptake

Project Summary Neurodevelopmental disorders such as cerebral palsy (CP) and autism are chronic disabilities with no effective cure, resulting in significant personal, social and economic burden. Neuroinflammation, mediated by activated microglia and astrocytes, plays a key role in the pathogenesis of cerebral palsy (CP) and autism. Targeting activated microglia/astrocytes in the brain may offer such an opportunity. This is a challenge at multiple levels. Our preliminary studies suggest that, upon intravenous administration, poly(amidoamine) (PAMAM) dendrimers (~4 nm), cross the blood-brain barrier (BBB), and further accumulate selectively in activated microglia and astrocytes in the brain of newborn rabbits with CP, but not in age-matched healthy controls. Importantly, a single 10 mg/kg drug dose in the form of this dendrimer-N-acetyl cysteine conjugate (D- NAC) administered on the day of birth (3 days after injury) intravenously to rabbit kits with CP, resulted in a significant improvement in motor function, attenuation of activated microglia, and decrease in neuronal injury and improved myelination by 5 days. Building on these promising findings, the long-term goal of this research is to develop dendrimer-based therapeutic approaches for the sustained postnatal treatment of neuroinflammation in CP. This will be achieved using the following specific aims: (1) determine whether increasing blood circulation time of dendrimers and using ligand targeting will improve microglial uptake and retention; (2) evaluate the toxicity of the dendrimer vehicle, and pharmacokinetics of NAC conjugated to dendrimers; (3) assess the sustained efficacy of the D- NAC conjugates, in improving motor function, decreasing microglial activation and brain injury up to 30 days. This study is significant because it: (1) explores the potential of targeted post-natal therapy in CP for improvement in motor phenotype, which has been a big challenge; (2) exploits the pathology-dependent differential uptake of PAMAM dendrimers by cells involved in neuroinflammation in CP; (3) will enable sustained attenuation of neuroinflammation during a crucial phase of brain development by providing tailored drug release; (4) uses NAC, a drug with a good safety profile in the perinatal and neonatal period, which can enable clinical translation. This study is innovative, because: (1) we evaluate therapeutic options in the postnatal period for a prenatal insult, to effect an improvement in motor function, with significant implications; (2) we seek to develop nanotherapeutic applications in the perinatal and neonatal period. Pediatric illnesses are often underserved by novel drug delivery technologies, which focus primarily on adults. This is the first study to bring nanotherapeutic approaches to childhood disorders such as CP.

项目摘要 神经发育障碍，如脑性瘫痪(CP)和自闭症，是慢性残疾，没有 有效治疗，造成重大的个人、社会和经济负担。神经炎症，由 活化的小胶质细胞和星形胶质细胞在脑性瘫痪(CP)和自闭症的发病机制中起关键作用。 靶向大脑中激活的小胶质细胞/星形胶质细胞可能提供这样的机会。这是一项挑战 多个级别。我们的初步研究表明，静脉给药时，聚酰胺胺 (PAMAM)树状大分子(~4 nm)，穿过血脑屏障(BBB)，进一步选择性地在 脑性瘫痪新生兔脑内小胶质细胞和星形胶质细胞的激活，而年龄匹配的健康兔则不激活 控制。重要的是，这种树状大分子-N-乙酰半胱氨酸结合物(D-C)形式的单次10毫克/公斤的药物剂量。 NAC)在出生当天(受伤后3天)静脉注射给患有CP的兔套件，导致 运动功能显著改善，激活的小胶质细胞减少，神经元损伤减轻 髓鞘形成时间延长5天。 在这些有希望的发现的基础上，这项研究的长期目标是开发基于树枝状大分子的 脑性瘫痪产后持续治疗神经炎的治疗方法。这将会实现的 使用以下具体目标：(1)确定是否增加树枝状大分子的血液循环时间和 使用配体靶向将改善小胶质细胞的摄取和滞留；(2)评估树枝状大分子的毒性 与树枝状大分子偶联的NAC的药代动力学；(3)评价D-DAC的持续疗效。 NAC结合物，在改善运动功能，减少小胶质细胞激活和脑损伤长达30天。 这项研究具有重要意义，因为它：(1)探索脑瘫产后靶向治疗的潜力。 运动表型的改善，这一直是一个很大的挑战；(2)利用病理依赖 参与慢性阻塞性肺疾病神经炎症的细胞对PAMAM树突状分子的不同摄取；(3)将使 在大脑发育的关键阶段通过提供量身定制的 药物释放；(4)使用NAC，这是一种在围产期和新生儿期具有良好安全性的药物，可以 启用临床翻译。这项研究是创新的，因为：(1)我们评估治疗方案 对于出生后时期的产前侮辱，影响运动功能的改善，具有重大意义； (2)我们寻求在围产期和新生儿期开发纳米治疗应用。儿科疾病 主要针对成年人的新型药物递送技术往往得不到足够的服务。这是第一次 研究将纳米治疗方法应用于儿童疾病，如CP。