Nanotherapies for the treatment of neurodevelopmental disorders.

描述(申请人提供)：神经发育障碍，如脑性瘫痪(CP)和自闭症是慢性残疾，没有有效的治疗方法，导致重大的个人、社会和经济负担。由激活的小胶质细胞和星形胶质细胞介导的神经炎症在脑性瘫痪(CP)和自闭症的发病机制中起着关键作用。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。这是一个多层面的挑战。我们的初步研究表明，静脉注射聚酰胺胺(PAMAM)树枝状大分子(~4 nm)，穿过血脑屏障(BBB)，进一步选择性地积聚在脑瘫新生兔脑内激活的小胶质细胞和星形胶质细胞中，而年龄匹配的健康对照组则没有。重要的是，这种树状大分子-N-乙酰半胱氨酸结合物(D-NAC)在出生当天(伤后3天)静脉注射给药10 mg/kg，可显著改善CP兔的运动功能，减少激活的小胶质细胞，减轻神经元损伤，并促进髓鞘形成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治疗方法，用于持续治疗CP的出生后神经炎。这将通过以下具体目标来实现：(1)确定延长树枝状大分子的血液循环时间和使用配体靶向是否将改善小胶质细胞的摄取和滞留；(2)评估树枝状大分子载体的毒性，以及与树枝状大分子偶联的NAC的药代动力学；(3)评估D-NAC结合物在改善运动功能、减少小胶质细胞激活和脑损伤方面的持续疗效，最长可达30天。这项研究具有重要意义，因为它：(1)探索产后靶向治疗对改善CP运动表型的潜力；(2)利用CP中参与神经炎症的细胞对PAMAM树突状分子的依赖病理进行的差异摄取；(3)通过提供量身定制的药物释放，使大脑发育的关键阶段能够持续缓解神经炎症；(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，可以使临床翻译成为可能。这项研究是创新的，因为：(1)我们评估出生后阶段对产前侮辱的治疗选择，以改善运动功能，具有重要意义；(2)我们寻求开发围产期和新生儿期的纳米治疗应用。儿科疾病往往得不到新的药物输送技术的帮助，这些技术主要针对成年人。这是第一项将纳米治疗方法应用于CP等儿童疾病的研究。

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.