权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Nanotherapies for the treatment of neurodevelopmental disorders.

用于治疗神经发育障碍的纳米疗法。

基本信息

批准号：
9257381
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
项目类别：
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/9257381
关键词：
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 Cysteine Dendrimers Development Diffuse Disease Disulfides Dose Drug Delivery Systems Drug Kinetics Economic Burden Esters Fluorescence Formulation Generations Goals Human Hydroxyl Radical Immunohistochemistry Impairment Inflammation Injury Intravenous 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 brain parenchyma clinical translation 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 therapeutic intervention novel therapeutics overexpression postnatal prenatal public health relevance receptor social uptake

项目摘要

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.

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，导致重大的个人，社会和经济负担。由活化的小胶质细胞和星形胶质细胞介导的神经炎症在脑瘫和自闭症的发病机制中起着关键作用。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。这是一个多层面的挑战。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（约4 nm），穿过血脑屏障（BBB），并进一步选择性地积累在活化的小胶质细胞和星形胶质细胞在新生兔脑CP，但不是在年龄匹配的健康对照。重要的是，在出生当天（损伤后3天）静脉内给予具有CP的兔试剂盒的这种树枝状聚合物-N-乙酰半胱氨酸缀合物（D-NAC）形式的单次10 mg/kg药物剂量导致运动功能的显著改善、活化的小胶质细胞的减弱、神经元损伤的减少和髓鞘形成的改善，持续5天。基于这些有希望的发现，本研究的长期目标是开发基于树枝状聚合物的治疗方法，用于CP神经炎症的持续产后治疗。（1）确定增加树枝状聚合物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保留;（2）评估树枝状聚合物媒介物的毒性和与树枝状聚合物缀合的NAC的药代动力学;（3）评估D-NAC缀合物在改善运动功能、减少小胶质细胞活化和脑损伤方面的持续功效长达30天。这项研究是重要的，因为它：（1）探索了CP的靶向产后治疗改善运动表型的潜力，这一直是一个很大的挑战;（2）利用了CP中神经炎症相关细胞对PAMAM树枝状聚合物的病理依赖性差异摄取;（3）通过提供定制的药物释放，将能够在大脑发育的关键阶段持续减轻神经炎症;（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，可以实现临床转化。本研究具有创新性，因为：（1）我们评估了出生后产前损伤的治疗方案，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。儿科疾病往往没有得到新的药物输送技术的充分服务，这些技术主要集中在成人身上。这是第一项将纳米方法引入儿童疾病如CP的研究。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Accumulation and cellular localization of nanoparticles in an ex vivo model of acute lung injury.

急性肺损伤离体模型中纳米粒子的积累和细胞定位。

DOI：
10.1016/j.jss.2016.11.007
发表时间：
2017
期刊：
The Journal of surgical research
影响因子：
0
作者：
Grimm,JoshuaC;Zhang,Fan;Magruder,JonathanT;Crawford,ToddC;Mishra,Manoj;Rangaramanujam,KannanM;Shah,AshishS
通讯作者：
Shah,AshishS

Targeting Mitochondria in Tumor-Associated Macrophages using a Dendrimer-Conjugated TSPO Ligand that Stimulates Antitumor Signaling in Glioblastoma.