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: 8343916
• 负责人: Omolola Eniola-Adefeso
• 金额: $ 36.63万
• 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/8343916
• 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. PUBLIC HEALTH RELEVANCE: This application seeks to elucidate the relationship between particle material characteristics and their acquired plasma "protein corona" in prescribing their effective margination (localization and adhesion) to the vascular wall endothelium from bulk human blood flow relevant in several cardiovascular diseases. Targeted delivery of imaging/therapeutics to specific sites in the body can allow for the administration of highly potent therapeutics to diseased tissues without affecting healthy ones; thereby, enhancing drug efficacy with no deleterious side effects. This can lead to a significant decrease in the high mortality rate attributed to cardiovascular diseases and lowered healthcare cost associated with current treatments.

描述（由申请人提供）：本申请旨在阐明粒子物质与物理特征与血浆获得的蛋白电晕之间的关系，以从许多心血管疾病（CVD）中相关的大量血流开出其边缘（定位和粘附）到血管壁的边缘（定位和粘附）。通常，血管壁目标载体通过其成像和药物输送能力来改善CVD的治疗机会，这些功能可能会提供与增强影像学和/或药物释放的成像和/或定位相关的更安全，更有效的干预措施。几个血管内皮调节的过程，例如与大多数心血管疾病一样，慢性炎症和血管生成参与了动脉粥样硬化的病理。因此，通过疾病诱导的内皮细胞（EC）标记靶向治疗剂可以为旨在预防疾病或逆转既定疾病的疗法的成像和递送提供可行的非手术方法。有效的血管靶向载体必须成功地导航血流以达到靶标，包括能够避免免疫清除率，从细胞致密的血流中找到血管壁，并克服颠覆性力，以在目标部位结合。除了识别适当的目标表位外，还可以识别载体特性（包括尺寸，形状和表面特征），从而使最佳的载体定位以及与血管壁相互作用对此目标至关重要。在这里，我们假设Carrir材料特征及其随之而来的“蛋白质电晕”会影响载体系统的能力，除了调节免疫清除率外，载体系统将其定位并粘附在散装血流中。该假设是基于（1）我们的初步观察结果，即聚（乳酸 - 糖甘油）（PLGA）微球显示出对激活的EC单层的粘附显着较低，从人类血流相对于相同大小，配体涂层和表面电荷和表面电荷的相同聚苯乙烯球体相对于聚体流。尽管PLGA比血液略浓，而聚苯乙烯则是血液中的密度中性。 （2）最近的文献显示了覆盖的不同聚合物材料的纳米颗粒 具有相同的高PEG密度在其表面上吸收了不同水平和类型的蛋白质。拟议工作的具体目的是：评估（1）载体材料特征及其随之而来的等离子获得的蛋白电晕在人体血流中球形载体的差异差异中的作用； （2）材料类型和材料疏水性，表面涂层以及处方载体边缘的粒径和形状的耦合效果； （3）细胞载体相互作用和静电排斥/吸引力在血管中的作用 与其蛋白电晕相关的载体的明显边缘。据我们所知，拟议的工作将是探索转化化在几种CVD中相关的大量人体血流中不同可生物降解的聚合物载体在差异边缘中的作用的首次尝试，尤其是在动脉粥样硬化中的成像和治疗性干预中。我们拟议的工作的总体成功将为精致的血管靶向系统的工程提供一个扎实的科学框架，这些框架除了治疗心血管疾病以外还具有影响。 公共卫生相关性：该应用程序旨在阐明粒子材料特征与它们获得的血浆“蛋白电晕”之间的关系，以在几种心血管疾病中与大量人体血液相关的血管壁内皮的有效边缘（定位和粘附）处方对血管壁内皮的关系。将成像/治疗剂的靶向递送到体内特定部位可以允许对患病的组织进行高度有效的治疗，而不会影响健康的组织；从而增强药物功效而没有有害副作用。这可能导致归因于心血管疾病的高死亡率显着降低，并降低了与当前治疗相关的医疗保健成本。