Role of carrier plasma protein corona in their vascular wall localization

描述（由申请人提供）：本申请旨在阐明颗粒材料和物理特性之间的关系，以及它们的血浆获得性蛋白冠在规定它们在许多心血管疾病（cvd）相关的大量血流中与血管壁的边界（定位和粘附）。总的来说，血管壁靶向载体通过其成像和药物输送能力为改善心血管疾病的治疗提供了很大的机会，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、更高效和有效的干预。一些血管内皮调节的过程，如慢性炎症和血管生成，与动脉粥样硬化的病理有关，与大多数心血管疾病一样；因此，通过疾病诱导的内皮细胞（EC）标记物靶向治疗可以提供一种可行的、非手术的方法来成像和递送治疗药物，旨在预防疾病或逆转已建立的疾病。有效的血管靶向载体必须成功地通过血流到达靶点，包括能够避免免疫清除，从细胞密集的血流中找到血管壁，并克服破坏力在靶点结合。除了确定合适的靶表位外，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和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，除了调节免疫清除外，载体材料的特性及其随之而来的“蛋白质冠”还会影响载体系统在大容量血流中定位和粘附血管壁的能力。这一假设基于(1)我们的初步观察，即相对于具有相同尺寸、配体涂层和表面电荷的聚苯乙烯球，聚乳酸-共乙醇酸（PLGA）微球对来自人体血流的活化EC单层的粘附性明显较低；虽然PLGA的密度比血液稍高，而聚苯乙烯在血液中的密度是中性的；(2)近期文献显示不同高分子材料包覆的纳米颗粒

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.