Vascular‐targeted nanocarriers: design considerations and strategies for successful treatment of atherosclerosis and other vascular diseases

Advanced Review

William J. Kelley, Hanieh Safari, Genesis Lopez‐Cazares, Omolola Eniola‐Adefeso

Published Online: May 19 2016

DOI: 10.1002/wnan.1414

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Vascular‐targeted nanocarriers are an attractive option for the treatment of a number of cardiovascular diseases, as they allow for more specific delivery and increased efficacy of many small molecule drugs. However, immune clearance, limited cellular uptake, and particle‐cell dynamics in blood flow can hinder nanocarrier efficacy in many applications. This review aims to investigate successful strategies for the use of vascular‐targeted nanocarriers in the treatment of cardiovascular diseases such as atherosclerosis. In particular, the review will highlight strategies employed for actively targeting the components of the atherosclerotic plaque, including endothelial cells, macrophages, and platelets and passive targeting via endothelial permeability, as well as design specifications (such as size, shape, and density) aimed at enhancing the ability of nanocarriers to reach the vascular wall. WIREs Nanomed Nanobiotechnol 2016, 8:909–926. doi: 10.1002/wnan.1414 This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Cardiovascular Disease Therapeutic Approaches and Drug Discovery > Nanomedicine for Neurological Disease Nanotechnology Approaches to Biology > Nanoscale Systems in Biology

Particle‐cell dynamics in blood flow and their influence on margination. Nanosized carriers, both spherical and rod‐like, are more likely to become entrapped in the RBC core, and are unable to effectively marginate to the vascular wall. Larger particles, 1‐2 µm in size, are pushed toward the cell‐free layer, where they are able to interact with the endothelium. Rod‐like microparticles may exhibit enhanced margination due to an increased drift force and tumbling motion in flow.

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Depiction of atherosclerotic plaque and nanoparticle active targeting mechanisms. During atherosclerosis, the endothelial cells become inflamed as low‐density lipoproteins (LDLs) accumulate. LDLs are oxidized and taken up by macrophages, which then differentiate into foam cells. Inflammatory molecules are released, promoting leukocyte and platelet adhesion leading to smooth muscle cell recruitment. Shown are three active targeting mechanisms: (a) targeting of inflammatory surface receptors, (b) multivalent targeting of exposed collagen (post‐surgical intervention) and platelets, and (c) high‐density lipoprotein mimetic targeting utilizing the reverse cholesterol transport mechanism. NP = nanoparticle.

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Passive targeting approach for cardiovascular diseases. Inflammation and endothelial dysfunction are characteristics demonstrated by damaged vascular tissues. Here are displayed four types of nanoparticles that take advantage of the ‘Enhanced permeability effect (EPR).’ One drawback of this approach is that the particle may become cleared before reaching the diseased endothelium. The addition of PEG and zwitterions to the surface of the particles has shown to decrease plasma protein adsorption increasing circulation time and decrease clearance. The third approach depicted is the application of a magnetic field used to direct nanoparticles throughout the body.

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