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

Inflammatory Cells for Transport of Therapeutic Polypeptides Across the BBB

用于跨 BBB 运输治疗性多肽的炎症细胞

基本信息

批准号：
8329677
负责人：
ELENA BATRAKOVA
金额：
$ 29.33万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-29 至 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8329677
关键词：
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine Adverse effects Animals Anti-Inflammatory Agents Anti-inflammatory Attenuated Aziridines Biodistribution Blood Blood - brain barrier anatomy Bone Marrow Brain Cells Central Nervous System Diseases Characteristics Charge Chemotaxis Complex Coupled Disease model Dopamine Agonists Drug Kinetics Dyskinetic syndrome Emission-Computed Tomography Encephalitis Endocytosis Endothelial Cells Enzymes Ethylene Glycols Exocytosis Extravasation Generations Hallucinations In Vitro Inflammation Inflammatory Inflammatory Response Ionic Strengths Kinetics Lead Length Longitudinal Studies Mediating Methods Micelles Microglia Monitor Mononuclear Morphology Mus Nerve Degeneration Neurodegenerative Disorders Neurotoxins Neurotransmitters Oxidation-Reduction Palliative Care Parkinson Disease Particle Size Patients Penetration Phagocytes Pharmaceutical Preparations Photons Polymers Preparation Process Property Proteins Reactive Oxygen Species Sampling Studies Scheme Series Signal Transduction Site Stream Structure System Testing Therapeutic Time Tissue Sample Toxic effect Treatment Efficacy base catalase chemokine copolymer crosslink enzyme activity ethylene glycol human disease improved in vitro Model in vivo in vivo Model macrophage magnetic resonance spectroscopic imaging monocyte monolayer nanoparticle neuroimaging neuroinflammation neuroprotection new technology novel polyion polypeptide public health relevance response scavenger receptor therapeutic target uptake

项目摘要

DESCRIPTION (provided by applicant): Currently, there are no curative or interdictive therapies available for Parkinson's disease (PD), and only palliative therapies such as replacement strategies for missing neurotransmitters exist. The main obstacle is the blood brain barrier (BBB) that severely limits the brain penetration of therapeutics, which can be successfully used for PD therapy. In particular, BBB is practically impermeable for polypeptides involved in anti-inflammatory neuroprotection. Nevertheless, there is a class of inflammatory response cells that have extraordinary ability to cross the BBB due to their increased margination and extravasation. A long-term objective of this proposal is to develop a targeted cell-mediated delivery of therapeutic polypeptides to the brain to attenuate neuroinflammation and produce neuroprotection in patients with PD. Specifically, we aimed to load mouse bone-marrow derived monocytes (BMM) ex vivo with an anti-inflammatory polypeptide, catalase, and administer these cells into the blood stream. To protect the enzyme against degradation inside the host cells, catalase will be coupled with a synthetic polyelectrolyte of opposite charge. The drug-loaded BMM will migrate across the BBB in vivo toward the inflammation signal and release the nanoparticles that attenuate inflammation. We hypothesize that 1) catalase-incorporated nanoparticles will be taken by BMM through the accelerated endocytosis; 2) loaded BMM will migrate across the BBB toward the inflammation signal, and 3) the nanoparticles will be discharged by exocytosis from the carrier cells in the brain, where catalase will produce its neuroprotection effect. Incorporation of catalase into nanoparticles will preserve its activity inside BMM, while using cell-mediated delivery will reduce its immunogenecity and target the therapeutic polypeptide to the brain. To test this hypothesis, first, we will synthesize series of block copolymers to obtain catalase/polymer nanoparticles that protect enzymatic activity of catalase inside the cells, and optimize their composition with maximal loading efficiency and sustained release of the polypeptide from BMM. Second, we will characterize the biodistribution and therapeutic efficacy of catalase nanoparticles delivered by BMM in the PD in vivo model. It is anticipated that these studies will lead to the developing a new technology based on cell- mediated active delivery of therapeutic polypeptides that attenuate neuroinflammation and produce neuroprotection in patients with PD. Public Health Relevance: It is anticipated that these studies will lead to the developing a new technology based on cell-mediated active delivery of therapeutic polypeptides that attenuate neuroinflammation and produce neuroprotection in patients with PD.

描述(申请人提供)：目前，帕金森氏病(PD)没有根治或阻断疗法，只有姑息疗法，如缺失神经递质的替代策略。主要的障碍是血脑屏障(BBB)，它严重限制了治疗药物的脑渗透，可以成功地用于帕金森病的治疗。特别是，血脑屏障对参与抗炎神经保护的多肽几乎是不透性的。然而，有一类炎性反应细胞具有非凡的穿越血脑屏障的能力，这是因为它们增加了边缘和外渗。这项建议的长期目标是开发一种有针对性的细胞介导的治疗性多肽输送到脑内，以减轻帕金森病患者的神经炎症并产生神经保护作用。具体地说，我们的目标是在体外将抗炎多肽过氧化氢酶加载到小鼠骨髓来源的单核细胞(BMM)中，并将这些细胞注入血液。为了防止酶在宿主细胞内降解，过氧化氢酶将与相反电荷的合成聚电解质偶联。载药的骨髓基质将在体内跨血脑屏障向炎症信号迁移，并释放减轻炎症的纳米颗粒。我们假设1)含有过氧化氢酶的纳米颗粒将通过加速的内吞作用被骨髓基质细胞摄取；2)装载的骨髓基质将通过血脑屏障向炎症信号迁移；3)纳米颗粒将通过胞吐从脑内的载体细胞中排出，在那里过氧化氢酶将产生其神经保护作用。将过氧化氢酶掺入纳米粒将保持其在BMM内的活性，而使用细胞介导的递送将降低其免疫原性，并将治疗性多肽靶向大脑。为了验证这一假设，首先，我们将合成一系列嵌段共聚物，以获得保护细胞内过氧化氢酶活性的过氧化氢酶/聚合物纳米粒子，并优化其组成，使其具有最大的负载效率和多肽从BMM中的持续释放。其次，我们将表征由BMM运送的过氧化氢酶纳米粒在帕金森病体内模型中的生物分布和治疗效果。预计这些研究将导致开发一种基于细胞介导的主动递送治疗性多肽的新技术，以减轻帕金森病患者的神经炎症并产生神经保护作用。公共卫生相关性：预计这些研究将导致开发一种基于细胞介导的主动递送治疗性多肽的新技术，该技术可以减轻帕金森病患者的神经炎症并产生神经保护。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Sensitizing of gemcitabine-resistant human leukemia cells by stearoyl gemcitabine nanoparticles .

硬脂酰吉西他滨纳米颗粒对吉西他滨耐药的人白血病细胞进行敏化。

DOI：
10.2217/nnm.11.146
发表时间：
2011
期刊：
Nanomedicine (London, England)
影响因子：
0
作者：
Batrakova,ElenaV
通讯作者：
Batrakova,ElenaV

Overcoming multidrug resistance using silica nanoparticles PEG-b-PLA polymeric micelles loaded with doxorubicin.

使用负载阿霉素的二氧化硅纳米颗粒 PEG-b-PLA 聚合物胶束克服多药耐药性。

DOI：
发表时间：
2011
期刊：
Nanomedicine (London, England)
影响因子：
0
作者：
Batrakova,ElenaV
通讯作者：
Batrakova,ElenaV

Macrophages with cellular backpacks for targeted drug delivery to the brain.

DOI：
10.1016/j.biomaterials.2017.06.017
发表时间：
2017-09
期刊：
Biomaterials
影响因子：
14
作者：
Klyachko NL;Polak R;Haney MJ;Zhao Y;Gomes Neto RJ;Hill MC;Kabanov AV;Cohen RE;Rubner MF;Batrakova EV
通讯作者：
Batrakova EV

Using exosomes, naturally-equipped nanocarriers, for drug delivery.

DOI：
10.1016/j.jconrel.2015.07.030
发表时间：
2015-12-10
期刊：
Journal of controlled release : official journal of the Controlled Release Society
影响因子：
0
作者：
Batrakova EV;Kim MS
通讯作者：
Kim MS

Reversal of multidrug resistance by PEG-b-PLA polymeric micelles loaded with paclitaxel.

负载紫杉醇的 PEG-b-PLA 聚合物胶束逆转多药耐药性。