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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：
8134749
负责人：
ELENA BATRAKOVA
金额：
$ 28.65万
依托单位：
UNIVERSITY OF NEBRASKA MEDICAL CENTER
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 2012-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8134749
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（由申请人提供）：目前，帕金森病（PD）没有治愈性或阻断性治疗，仅存在姑息性治疗，如缺失神经递质的替代策略。主要障碍是血脑屏障（BBB），其严重限制了可成功用于PD治疗的治疗剂的脑渗透。特别地，BBB对于参与抗炎神经保护的多肽几乎是不可渗透的。然而，有一类炎症反应细胞由于其增加的边缘化和外渗而具有非凡的穿过BBB的能力。该提案的长期目标是开发治疗性多肽向脑的靶向细胞介导递送，以减轻PD患者的神经炎症并产生神经保护。具体而言，我们的目的是负载小鼠骨髓来源的单核细胞（BMM）离体与抗炎多肽，过氧化氢酶，并将这些细胞给药到血流中。为了保护酶在宿主细胞内不被降解，过氧化氢酶将与相反电荷的合成酶偶联。载药的BMM将在体内朝向炎症信号迁移穿过BBB，并释放减轻炎症的纳米颗粒。我们假设：1）过氧化氢酶掺入的纳米颗粒将通过加速的内吞作用被BMM摄取; 2）负载的BMM将穿过BBB向炎症信号迁移，以及3）纳米颗粒将通过胞吐作用从脑中的载体细胞中排出，其中过氧化氢酶将产生其神经保护作用。将过氧化氢酶并入纳米颗粒中将保留其在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过氧化氢酶/聚合物纳米颗粒，其保护细胞内过氧化氢酶的酶活性，并优化其组成，使其具有最大的负载效率和多肽从BMM的持续释放。其次，我们将在PD体内模型中表征由BMM递送的过氧化氢酶纳米颗粒的生物分布和治疗功效。预期这些研究将导致开发基于细胞介导的治疗性多肽的主动递送的新技术，所述治疗性多肽在患有PD的患者中减弱神经炎症并产生神经保护。公共卫生相关性：预期这些研究将导致开发基于细胞介导的治疗性多肽的主动递送的新技术，所述治疗性多肽在患有PD的患者中减弱神经炎症并产生神经保护。