Nanotherapies for the treatment of neurodevelopmental disorders.

描述（由申请人提供）：神经发育障碍如脑瘫（CP）和自闭症是慢性残疾，没有有效的治疗方法，造成重大的个人，社会和经济负担。激活的小胶质细胞和星形胶质细胞介导的神经炎症在脑瘫（CP）和自闭症的发病机制中起着关键作用。瞄准大脑中激活的小胶质细胞/星形胶质细胞可能提供这样一个机会。这是一个多层次的挑战。我们的初步研究表明，经静脉注射后，聚胺胺（PAMAM）树状大分子（~4 nm）穿过血脑屏障（BBB），并进一步选择性地积聚在新生CP兔大脑中活化的小胶质细胞和星形胶质细胞中，但在年龄匹配的健康对照中则没有。重要的是，在出生当天（损伤后3天）静脉给药10 mg/kg的树突状分子- n -乙酰半胱氨酸偶联物（D-NAC）给药，可以显著改善CP兔的运动功能，减少活化的小胶质细胞，减少神经元损伤，并改善5天的髓鞘形成。基于这些有希望的发现，本研究的长期目标是开发基于树突的治疗方法，用于CP的持续产后神经炎症治疗。这将通过以下具体目标来实现：(1)确定增加树突的血液循环时间和使用配体靶向是否会改善小胶质细胞的摄取和保留；(2)评估树状大分子载体的毒性，以及NAC与树状大分子缀合的药代动力学；(3)评估D-NAC偶联物在改善运动功能、减少小胶质细胞激活和脑损伤方面持续30天的疗效。本研究具有重要意义，因为：(1)探索了CP产后靶向治疗改善运动表型的潜力，这是一个很大的挑战；(2)利用CP中参与神经炎症的细胞对PAMAM树突的病理依赖性差异摄取；(3)将通过提供量身定制的药物释放，在大脑发育的关键阶段实现神经炎症的持续衰减；(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，可以进行临床转化。本研究具有创新性，因为：(1)我们评估了产前侮辱的产后治疗方案，以改善运动功能，具有重要意义；(2)我们寻求开发纳米治疗在围产期和新生儿期的应用。儿科疾病往往缺乏新的药物输送技术，主要集中在成人。这是首个将纳米治疗方法引入儿童疾病（如CP）的研究。

DESCRIPTION (provided by applicant): 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 significan 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.