Vascular-targeted particle binding efficacy in the presence of rigid red blood cells: Implications for performance in diseased blood

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Abstract

The field of drug delivery has taken an interest in combating numerous blood and heart diseases via the use of injectable vascular-targeted carriers (VTCs). However, VTC technology has encountered limited efficacy due to a variety of challenges associated with the immense complexity of the in vivo blood flow environment, including the hemodynamic interactions of blood cells, which impact their margination and adhesion to the vascular wall. Red blood cell (RBC) physiology, i.e., size, shape, and deformability, drive cellular distribution in blood flow and has been shown to impact VTC margination to the vessel wall significantly. The RBC shape and deformability are known to be altered in certain human diseases, yet little experimental work has been conducted towards understanding the effect of these alterations, specifically RBC rigidity, on VTC dynamics in physiological blood flow. In this work, we investigate the impact of RBCs of varying stiffnesses on the adhesion efficacy of particles of various sizes, moduli, and shapes onto an inflamed endothelial layer in a human vasculature-inspired, in vitro blood flow model. The blood rigid RBC compositions and degrees of RBC stiffness evaluated are analogous to conditions in diseases such as sickle cell disease. We find that particles of different sizes, moduli, and shapes yield drastically different adhesion patterns in blood flow in the presence of rigid RBCs when compared to 100% healthy RBCs. Specifically, up to 50% reduction in the localization and adhesion of non-deformable 2 μm particles to the vessel wall was observed in the presence of rigid RBCs. Interestingly, deformable 2 μm particles showed enhanced vessel wall localization and adhesion, by up to 85%, depending on the rigidity of RBCs evaluated. Ultimately, this work experimentally clarifies the importance of considering RBC rigidity in the intelligent design of particle therapeutics and highlights possible implications for a wide range of diseases relating to RBC deformability.

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Narla Mohandas, Patrick Gallagher (2008)

As a result of natural selection driven by severe forms of malaria, 1 in 6 humans in the world, more than 1 billion people, are affected by red cell abnormalities, making them the most common of the inherited disorders. The non-nucleated red cell is unique among human cell type in that the plasma membrane, its only structural component, accounts for all of its diverse antigenic, transport, and mechanical characteristics. Our current concept of the red cell membrane envisions it as a composite structure in which a membrane envelope composed of cholesterol and phospholipids is secured to an elastic network of skeletal proteins via transmembrane proteins. Structural and functional characterization of the many constituents of the red cell membrane, in conjunction with biophysical and physiologic studies, has led to detailed description of the way in which the remarkable mechanical properties and other important characteristics of the red cells arise, and of the manner in which they fail in disease states. Current studies in this very active and exciting field are continuing to produce new and unexpected revelations on the function of the red cell membrane and thus of the cell in health and disease, and shed new light on membrane function in other diverse cell types.

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Randall Toy, Pubudu Peiris, Ketan B Ghaghada … (2014)

Recent advances in nanoparticle technology have enabled the fabrication of nanoparticle classes with unique sizes, shapes and materials, which in turn has facilitated major advancements in the field of nanomedicine. More specifically, in the last decade, nanoscientists have recognized that nanomedicine exhibits a highly engineerable nature that makes it a mainstream scientific discipline that is governed by its own distinctive principles in terms of interactions with cells and intravascular, transvascular and interstitial transport. This review focuses on the recent developments and understanding of the relationship between the shape of a nanoparticle and its navigation through different biological processes. It also seeks to illustrate that the shape of a nanoparticle can govern its in vivo journey and destination, dictating its biodistribution, intravascular and transvascular transport, and, ultimately, targeting of difficult to reach cancer sites.

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Elasticity of nanoparticles influences their blood circulation, phagocytosis, endocytosis, and targeting.

Aaron Anselmo, Mengwen Zhang, Sunny Kumar … (2015)

The impact of physical and chemical modifications of nanoparticles on their biological function has been systemically investigated and exploited to improve their circulation and targeting. However, the impact of nanoparticles' flexibility (i.e., elastic modulus) on their function has been explored to a far lesser extent, and the potential benefits of tuning nanoparticle elasticity are not clear. Here, we describe a method to synthesize polyethylene glycol (PEG)-based hydrogel nanoparticles of uniform size (200 nm) with elastic moduli ranging from 0.255 to 3000 kPa. These particles are used to investigate the role of particle elasticity on key functions including blood circulation time, biodistribution, antibody-mediated targeting, endocytosis, and phagocytosis. Our results demonstrate that softer nanoparticles (10 kPa) offer enhanced circulation and subsequently enhanced targeting compared to harder nanoparticles (3000 kPa) in vivo. Furthermore, in vitro experiments show that softer nanoparticles exhibit significantly reduced cellular uptake in immune cells (J774 macrophages), endothelial cells (bEnd.3), and cancer cells (4T1). Tuning nanoparticle elasticity potentially offers a method to improve the biological fate of nanoparticles by offering enhanced circulation, reduced immune system uptake, and improved targeting.