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.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Biomaterials and Biointerfaces Study Section (BMBI)
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Danthi, Narasimhan
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University of Michigan Ann Arbor
Engineering (All Types)
Schools of Engineering
Ann Arbor
United States
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Sobczynski, Daniel J; Eniola-Adefeso, Omolola (2016) Effect of anticoagulants on the protein corona-induced reduced drug carrier adhesion efficiency in human blood flows. Acta Biomater :
Kelley, William J; Safari, Hanieh; Lopez-Cazares, Genesis et al. (2016) Vascular-targeted nanocarriers: design considerations and strategies for successful treatment of atherosclerosis and other vascular diseases. Wiley Interdiscip Rev Nanomed Nanobiotechnol 8:909-926
Namdee, Katawut; Sobczynski, Daniel J; Onyskiw, Peter J et al. (2015) Differential Impact of Plasma Proteins on the Adhesion Efficiency of Vascular-Targeted Carriers (VTCs) in Blood of Common Laboratory Animals. Bioconjug Chem 26:2419-28
Sobczynski, Daniel J; Fish, Margaret B; Fromen, Catherine A et al. (2015) Drug carrier interaction with blood: a critical aspect for high-efficient vascular-targeted drug delivery systems. Ther Deliv 6:915-34
Fish, Margaret B; Thompson, Alex J; Fromen, Catherine A et al. (2015) Emergence and Utility of Nonspherical Particles in Biomedicine. Ind Eng Chem Res 54:4043-4059
Sobczynski, Daniel J; Charoenphol, Phapanin; Heslinga, Michael J et al. (2014) Plasma protein corona modulates the vascular wall interaction of drug carriers in a material and donor specific manner. PLoS One 9:e107408