Nanotherapies for the treatment of neurodevelopmental disorders.

项目摘要 神经发育障碍，如脑瘫（CP）和自闭症是慢性残疾， 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瘫（CP）和自闭症的发病机制中起关键作用。 针对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。这是一个挑战， 多层次的我们的初步研究表明，静脉给药后，聚（酰胺胺） （PAMAM）树枝状聚合物（~4 nm），穿过血脑屏障（BBB），并进一步选择性地在脑组织中蓄积。 CP新生兔脑内小胶质细胞和星形胶质细胞活化，而同龄健康兔脑内无 对照重要的是，以这种树枝状聚合物-N-乙酰半胱氨酸缀合物（D-半胱氨酸）形式的单次10 mg/kg药物剂量， NAC）在出生当天（损伤后3天）静脉内给予CP兔套件，导致 运动功能显著改善，活化的小胶质细胞减少，神经元损伤减少 并在5天内改善髓鞘形成。 基于这些有希望的发现，这项研究的长期目标是开发基于树枝状聚合物的 治疗方法的持续产后治疗的神经炎症在CP。完成这项工作的方法是 使用以下具体目的：（1）确定是否增加树枝状聚合物的血液循环时间， 使用配体靶向将改善小胶质细胞的摄取和保留;（2）评估树枝状聚合物的毒性 载体和缀合至树枝状聚合物的NAC的药代动力学;（3）评估D-NAC的持续功效。 NAC结合物，改善运动功能，减少小胶质细胞活化和脑损伤长达30天。 本研究具有重要意义，因为它：（1）探索了CP的靶向产后治疗的潜力， 运动表型的改善，这一直是一个很大的挑战;（2）利用病理依赖性 参与CP神经炎症的细胞对PAMAM树枝状聚合物的差异摄取;（3）将使 在大脑发育的关键阶段，通过提供定制的 药物释放;（4）使用NAC，一种在围产期和新生儿期具有良好安全性的药物， 使临床翻译。这项研究是创新的，因为：（1）我们评估了治疗方案， 出生后时期的产前损伤，以改善运动功能，具有重要意义; (2)我们寻求在围产期和新生儿期开发纳米技术应用。儿科疾病 新的药物输送技术往往不能充分满足这些需求，因为这些技术主要针对成年人。这是第一 研究为儿童疾病如CP带来纳米方法。

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.