Role of carrier plasma protein corona in their vascular wall localization

载体血浆蛋白冠在血管壁定位中的作用

• 批准号: 8510724
• 负责人: Omolola Eniola-Adefeso
• 金额: $ 34.78万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-13 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8510724
• 关键词: Adhesions; Adverse effects; Affect; Animal Model; Atherosclerosis; Binding; Biocompatible Coated Materials; Biocompatible Materials; Biological Assay; Blood; Blood Cells; Blood Vessels; Blood flow; Cardiovascular Diseases; Cell Aggregation; Cell Wall; Cells; Characteristics; Charge; Chronic; Clinic; Coupled; Disease; Drug Delivery Systems; Electrophoresis; Electrostatics; Endothelial Cells; Endothelium; Engineering; Epitopes; Excision; Goals; Health Care Costs; Homing; Human; Hydrophobicity; Image; Image Enhancement; Individual; Inflammation; Kinetics; Lead; Ligands; Literature; Mass Spectrum Analysis; Metabolic Clearance Rate; Microspheres; Particle Size; Pathology; Pharmaceutical Preparations; Plasma; Plasma Proteins; Polymers; Polystyrenes; Process; Property; Proteins; Relative (related person); Research; Resolution; Retinal Cone; Role; Shapes; Site; Solid; Stream; Surface; System; Therapeutic; Therapeutic Intervention; Tissues; Two-Dimensional Polyacrylamide Gel Electrophoresis; Vascular Endothelium; Work; angiogenesis; base; caprolactone; cost; density; design; disorder prevention; drug efficacy; effective intervention; hemodynamics; immune clearance; improved; in vivo; iron oxide; monolayer; mortality; nanoparticle; novel therapeutics; particle; poly(lactide); pre-clinical research; retinal rods; success; surface coating; targeted delivery; therapeutic target

DESCRIPTION (provided by applicant): This application seeks to elucidate the relationship between particle material and physical characteristics and their plasma-acquired protein corona in prescribing their margination (localization and adhesion) to the vascular wall from bulk blood flow relevant in many cardiovascular diseases (CVDs). In general, vascular wall- targeted carriers offer great opportunities to improve the treatment of CVDs through their imaging and drug delivery capabilities that potentially provide safer, more efficient and effective interventio associated with enhancement of imaging and/or localization of drug release. Several vascular endothelium-regulated processes, e.g. chronic inflammation and angiogenesis, are involved in the pathology of atherosclerosis, as with most cardiovascular diseases; therefore, targeting therapeutics via disease-induced endothelial cell (EC) markers could provide a viable, non-surgical approach to imaging and delivery of therapeutics aimed at disease prevention or reversing established disease. Effective vascular-targeted carriers must successfully navigate the blood stream to reach the target, including being able to avoid immune clearance, find the vascular wall from the cell dense blood flow, and overcome disruptive forces to bind at the target site. In addition to identifying appropriate target epitope(s), identifying carrier propertis - including size, shape, and surface characteristics - that allow for optimum carrier localization and interaction with the vascular wall is crucial to this goal. Here, we hypothesize that the carrir material characteristics and its ensuing "protein corona" impact the capacity for a carrier system to localize and adhere to the vessel wall from bulk blood flow in addition to modulating immune clearance. This hypothesis is based on (1) our preliminary observation that poly(lactide-co-glycolic) (PLGA) microspheres show significantly lower adhesion to activated EC monolayers from human blood flow relative to polystyrene spheres of the same size, ligand coating and surface charge; though PLGA is slightly denser than blood while polystyrene is density-neutral in blood; and (2) recent literature that show nanoparticles of different polymeric materials coated with the same high PEG density absorbed different levels and types of proteins on their surfaces. The specific aims of the proposed work are: to evaluate (1) the role of carrier material characteristics and their ensuing plasma-acquired protein corona in the differential margination of spherical carriers from human blood flow; (2) the coupled effect of material type and material hydrophobicity, surface coating, and particle size and shape in prescribing carrier margination; and (3) the role of cell-carrier interaction and electrostatic repulsion/attraction at the vascular wall in the distinct margination of carriers associated with their protein corona. To our knowledge, the proposed work would be the first attempt to explore the role of opsonization in the differential margination of different biodegradable polymeric carriers in bulk human blood flow relevant in several CVDs, particularly for imaging and therapeutic intervention in atherosclerosis. The overall success of our proposed work would provide a solid scientific framework for the engineering of sophisticated vascular-targeted systems that would have implications beyond treating cardiovascular diseases.

描述（由申请人提供）：本申请旨在阐明颗粒材料和物理特性及其血浆获得性蛋白冠之间的关系，以规定其与许多心血管疾病相关的大量血流的边缘（定位和粘附）到血管壁的关系（ CVD）。一般来说，血管壁靶向载体通过其成像和药物递送能力提供了改善CVD治疗的巨大机会，这些能力可能提供与增强成像和/或药物释放定位相关的更安全、更有效和更有效的干预。几种血管内皮调节过程，例如与大多数心血管疾病一样，慢性炎症和血管生成参与动脉粥样硬化的病理学；因此，通过疾病诱导的内皮细胞（EC）标记物进行靶向治疗可以提供一种可行的非手术方法来成像和提供旨在预防疾病或逆转既定疾病的治疗方法。有效的血管靶向载体必须成功地引导血流到达目标，包括能够避免免疫清除，从细胞密集的血流中找到血管壁，并克服破坏力以结合在目标位点。除了确定适当的目标表位外，确定载体特性（包括大小、形状和表面特征）以实现最佳载体定位以及与血管壁的相互作用对于实现这一目标至关重要。在这里，我们假设载体材料特性及其随之而来的“蛋白冠”除了调节免疫清除之外，还影响载体系统从大量血流中定位和粘附到血管壁的能力。这一假设基于 (1) 我们的初步观察，即相对于相同尺寸、配体涂层和表面电荷的聚苯乙烯球体，聚丙交酯-乙醇酸共聚物 (PLGA) 微球对人体血流中活化的 EC 单层的粘附力显着降低;尽管 PLGA 的密度比血液稍大，而聚苯乙烯在血液中呈密度中性； (2) 最近的文献显示不同聚合物材料涂覆的纳米颗粒 相同的高PEG密度在其表面吸收了不同水平和类型的蛋白质。拟议工作的具体目标是：评估（1）载体材料特性及其随后的血浆获得性蛋白冠在球形载体与人体血流的差异边缘化中的作用； (2) 材料类型和材料疏水性、表面涂层以及颗粒尺寸和形状在规定载体边缘方面的耦合效应； (3)细胞-载体相互作用和静电排斥/吸引在血管中的作用 与蛋白质冠相关的载体的明显边缘中的壁。据我们所知，拟议的工作将是首次尝试探索调理作用在与多种CVD相关的大量人体血流中不同可生物降解聚合物载体的差异边缘化中的作用，特别是对于动脉粥样硬化的成像和治疗干预。我们提出的工作的总体成功将为复杂的血管靶向系统的工程提供坚实的科学框架，其影响将超出治疗心血管疾病的范围。