Postnatal combination therapy for cerebral palsy

描述(由申请人提供)：母体炎症导致的围产期脑损伤与神经发育障碍有关，如脑瘫(CP)和自闭症谱系障碍。脑性瘫痪是一种慢性儿童残疾，没有有效的治疗方法，导致严重的个人、社会和经济负担。由激活的小胶质细胞和星形胶质细胞引起的神经炎症在CP的发病机制中起着关键作用。以这些细胞为靶点可能会使持续治疗持续到成年。我们的初步研究表明，静脉注射端羟基聚酰胺胺(PAMAM)树状大分子(~4 nm)可使其选择性积聚在新生兔脑内激活的小胶质细胞和星形胶质细胞中。 患有神经炎症和CP，但在年龄匹配的健康对照组中不存在。更重要的是，出生当天(伤后3天)静脉注射树突状大分子-N-乙酰半胱氨酸偶联物(D-NAC)10 mg/kg的药物，可显著改善CP兔的运动功能和髓鞘形成，减少激活的小胶质细胞，减少神经元损伤5天。在这些有希望的发现的基础上，我们的长期目标是开发有针对性的纳米治疗方法，用于持续的、产后的CP治疗，改善持续到成年(在兔模型中为约1个月)。我们建议使用树状大分子-NAC和树状大分子-米诺环素(D-NAC+D-Mino)的鸡尾酒来多管齐下减轻损伤。我们的总体假设是，联合治疗将提供NAC(快速释放)和米诺环素(缓释)的靶向细胞内释放。第一个目标是(D-NAC+D-Mino)结合物的制备和表征，第二个目标是研究NAC和米诺环素在脑、血浆和其他主要器官中的毒性、药代动力学和生物分布。目的3将集中于通过这种出生后的联合治疗所取得的持续疗效的纵向评估，直到30天(当兔的主要神经功能已经发生发展时)。这项研究意义重大，因为它首次探索了纳米技术在一种衰弱的儿童疾病中的应用，建立在积极的初步结果的基础上/这项建议对RFA的配方做出了回应，因为它直接 涉及儿科纳米技术、靶组织/细胞给药、持续给药、联合治疗和减少副作用等领域。

DESCRIPTION (provided by applicant): Maternal inflammation-induced perinatal brain injury has been implicated in neurodevelopmental disorders such as cerebral palsy (CP) and autism spectrum disorders. CP is a chronic childhood disability with no effective cure, resulting in significant personal, social and economic burden. Neuroinflammation, caused by activated microglia and astrocytes, plays a key role in the pathogenesis of CP. Targeting these cells may enable sustained therapies till adulthood. Our preliminary studies suggest that intravenous administration of a hydroxyl-terminated poly(amidoamine) (PAMAM) dendrimer (~4 nm) results in its selective accumulation in activated microglia and astrocytes in the brain of newborn rabbits with neuroinflammation and CP, but not in age-matched healthy controls. More importantly, a single 10 mg/kg drug dose in the form of dendrimer-N-acetyl cysteine conjugate (D-NAC) intravenously administered on the day of birth (3 days after injury) to rabbit kits with CP, resultd in a significant improvement in motor function and myelination, attenuation of activated microglia, and decrease in neuronal injury by 5 days. Building on these promising findings, our long-term goal is to develop targeted nanotherapeutic approaches for the sustained, post-natal treatment of CP, where improvements persist till adulthood (~1 month in the rabbit model). We propose using a cocktail of dendrimer-NAC and dendrimer-minocycline (D-NAC+D-Mino) for a multipronged approach to attenuate the injury. Our overall hypothesis is that the combination therapy will provide targeted intracellular release of NAC (fast release) and minocycline (sustained release). The first aim relates to the preparation and characterization of (D-NAC+D-Mino) conjugates, while the second aim focuses on the toxicity, pharmacokinetics and biodistribution of NAC and minocycline delivered through the conjugate, in the brain, plasma, and other major organs. Aim 3 will focus on the longitudinal evaluation of the sustained efficacy achieved through this postnatal, combination therapy up to 30 day (when development of major neurologic functions has occurred in rabbits). This study is significant, because it explores applications of nanotechnology for the first time to a debilitating childhood disease, building on positive preliminary results/ This proposal is responsive to the formulations RFA since it directly relates to areas of nanotechnology in pediatrics, delivery to target tissues/cells, sustained delivery, combination therapy, and reducing side effects.