Role of carrier plasma protein corona in their vascular wall localization

描述(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的蛋白质电晕之间的关系，以规定它们与许多心血管疾病(CVD)相关的大量血流对血管壁的边缘作用(定位和粘连)。总体而言，血管壁靶向载体通过其成像和药物输送能力提供了改善心血管疾病治疗的巨大机会，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。与大多数心血管疾病一样，动脉粥样硬化的病理过程涉及几个血管内皮调节过程，如慢性炎症和血管生成；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、非手术的方法来成像和提供旨在预防疾病或逆转既定疾病的治疗药物。有效的血管靶向载体必须成功地导航血流才能到达靶点，包括能够避免免疫清除，从细胞密集的血流中找到血管壁，以及克服干扰力量在靶点结合。除了确定合适的靶表位(S)外，确定载体特性--包括大小、形状和表面特征--以实现最佳的载体定位和与血管壁的相互作用对实现这一目标至关重要。在这里，我们假设载体材料的特性及其随之而来的“蛋白质冠状”除了调节免疫清除外，还会影响载体系统从大量血流中定位和附着于血管壁的能力。这一假说是基于(1)我们的初步观察，即聚丙交酯-乙醇酸(PLGA)微球与人体血液中活化的EC单层的粘附性明显低于相同尺寸、配体涂层和表面电荷的聚苯乙烯微球；尽管PLGA的密度略高于血液，而聚苯乙烯在血液中是密度中性的；以及(2)最近的文献显示，不同聚合物材料的纳米颗粒被包裹 在相同的高聚乙二醇密度下，其表面吸附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的蛋白质电晕在球形载体与人体血流的不同边缘形成中的作用；(2)材料类型和材料疏水性、表面涂层以及颗粒大小和形状对载体边缘形成的耦合效应；以及(3)细胞-载体相互作用和血管处静电排斥/吸引的作用。 壁上有明显的边缘，与它们的蛋白质冠状载体相关。据我们所知，这项拟议的工作将是首次尝试探索调理作用在不同生物可降解聚合物载体在与几种心血管疾病相关的大量人体血流中的不同边际作用中的作用，特别是在动脉粥样硬化的成像和治疗干预方面。我们提议的工作的总体成功将为设计复杂的血管靶向系统提供坚实的科学框架，这将具有治疗心血管疾病以外的影响。 公共卫生相关性：本应用旨在阐明粒子材料特性与其获得的血浆“蛋白质日冕”之间的关系，以规定它们与血管壁内皮细胞的有效结合(定位和黏附)与几种心血管疾病相关的大量人体血流。有针对性地将成像/治疗药物输送到身体的特定部位，可以在不影响健康组织的情况下，对疾病组织给予高度有效的治疗药物，从而提高药物疗效，而不会产生有害的副作用。这可以显著降低心血管疾病的高死亡率，并降低与当前治疗相关的医疗成本。

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.