Particle Margination and Its Implications on Intravenous Anticancer Drug Delivery

Abstract

Abstract. "Margination" refers to the movement of particles in flow toward the walls of a channel. The term was first coined in physiology for describing the behavior of white blood cells (WBCs) and platelets in blood flow. The margination of particles is desirable for anticancer drug delivery because it results in the close proximity of drug-carrying particles to the endothelium, where they can easily diffuse into cancerous tumors through the leaky vasculature. Understanding the fundamentals of margination may further lead to the rational design of particles and allow for more specific delivery of anticancer drugs into tumors, thereby increasing patient comfort during cancer treatment. This paper reviews existing theoretical and experimental studies that focus on understanding margination. Margination is a complex phenomenon that depends on the interplay between inertial, hydrodynamic, electrostatic, lift, van der Waals, and Brownian forces. Parameters that have been explored thus far include the particle size, shape, density, stiffness, shear rate, and the concentration and aggregation state of red blood cells (RBCs). Many studies suggested that there exists an optimal particle size for margination to occur, and that nonspherical particles tend to marginate better than spherical particles. There are, however, conflicting views on the effects of particle density, stiffness, shear rate, and RBCs. The limitations of using the adhesion of particles to the channel walls in order to quantify margination propensity are explained, and some outstanding questions for future research are highlighted.

Direct Tracking of Particles and Quantification of Margination in Blood Flow

“…Although adhesion and margination are related, evaluating margination based on the number of adhered particles could be further complicated by factors such as hydrodynamic drag, the densities of ligands and receptors grafted onto both the particle surface and the wall channel, the particle shape and contact orientation, and the particle size relative to the CFL (10,20,21). Particles may have detached from the wall due to collisions with blood cells or increasing wall shear rate.…”

“…Tumor sites are generally characterized by 1) leaky vasculature, which allows drugcarrying particles to diffuse into them, and 2) a lack of lymphatics, which allows these particles to remain inside the tumor. This so-called enhanced permeability and retention effect (8) further opens up the possibility of delivering chemotherapeutic drugs passively and more specifically to tumor sites, thereby limiting any damage to healthy tissues (9,10). A number of recent experimental (3,7,(11)(12)(13)(14)(15)(16)(17) and theoretical (18)(19)(20)(21)(22)(23) studies have suggested that particles of certain sizes and shapes have a higher margination propensity.…”

“…Particles may have detached from the wall at higher flow rates due to increasing hydrodynamic drag and/or collision with RBCs (3). In addition to particle size and flow rate, margination also depends on other factors such as particle shape, density, and stiffness, as well as blood hematocrit (10). Detailed reviews on margination and the effects of each of these factors are available (10,37).…”

“…First, all previous experimental studies, with only two exceptions (7,38), assessed margination propensity based on the number density, or, more precisely, the fluorescence intensity, of fluorescent particles that adhered to the channel wall after a particle suspension and subsequently a buffer solution passed through the channel (3,(11)(12)(13)(14)(16)(17)(18)39). Although adhesion is related to margination, adhesion also depends on other factors such as hydrodynamic drag, the densities of ligands and receptors grafted onto the particle surface and the wall channel, the particle shape and contact orientation, and the particle size relative to the CFL (10,16,17,20,21). In this work, the margination propensity was quantified based on the direct tracking of individual particles.…”

Calibration-Quality Cancer Nanotherapeutics

“…In terms of the particle circulation profiles, margination (defined as the movement of particles in flow toward the walls of the blood vessel) enhances the particles chances to extravasate through the leaky tumor vasculature and enter the tumor. Work-both empirical and theoretical-has been conducted in this area, comparing margination rates of spherical and nonspherical micro-and nanoparticles [20,22,26,27]. In general, nonspherical particles with higher aspect ratios marginate more readily than spherical particles.…”