The effects of particle size, density and shape on margination of nanoparticles in microcirculation

Abstract

In the recent past, remarkable advances in nanotechnology have generated nanoparticles of different shapes and sizes, which have been shown to exhibit unique properties suitable for biomedical applications such as cancer therapy and imaging. Obviously, all nanoparticles are not made equal. This becomes evident when we consider their transport behavior under blood flow in microcirculation. In this work, we evaluated the effect of critical physical characteristics such as the particle shape, size and density on a nanoparticle’s tendency to marginate towards the vessel walls in microcirculation using an in vitro model. The wall-deposition of nanoparticles was tested in a fibronectin-coated microfluidic channel at a physiologically relevant flow rate. Different classes of nanoparticles (liposome, metal particles) of different sizes (60–130 nm), densities (1–19 g/mL) and shapes (sphere, rod) displayed significantly different deposition as a result of different margination rates. The smaller-sized and the oblate-shaped particles displayed a favorable behavior as indicated by their higher margination rates. Notably, the particle density showed an even more essential role, as it was observed that the lighter particles marginated significantly more. Since nanoparticles must escape the flow in order to approach the vascular bed and subsequently extravascular components for meaningful interactions, the design of nanoparticles strongly affects their margination, a key factor for their ultimate in vivo effectiveness.

Direct Tracking of Particles and Quantification of Margination in Blood Flow

“…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. This would facilitate the diffusion of these particles into tumor sites by allowing them to reach the leaky blood vessel walls and, ultimately, the tumors.…”

“…A number of experimental (3,7,(11)(12)(13)(14)(15)(16)(17) and theoretical (19,(21)(22)(23) studies have explored the effect of varying particle size on the margination propensity of particles. Several studies suggested that larger particles marginate much more readily than smaller particles, and that there is an optimal particle size for margination (3,12,14,15,19,22,23).…”

“…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.…”

Synthesis, Functionalization, and Design of Magnetic Nanoparticles for Theranostic Applications

“…In the matter of size effect on margination behavior, several studies have been reported on increasing the margination propensity by increasing the diameter of nanoparticles, [15,466] however, there is no agreement on the optimal size for margination. [467] It has been shown by several studies that nanoparticles of ≈50 nm in size achieve an optimal cellular uptake. [468] Such nanoparticles appear to have the highest internalization and modest exocytosis rates, [469] while nanoparticles with hydrodynamic sizes larger than 60 nm are poorly taken up by tumor cells.…”

Particle Targeting in Complex Biological Media

“…[179] However, if the particles are below a critical size (typically <100 nm), margination has been observed to increase again. [177,180] This behavior has been attributed to differences in the transportation mechanisms of particles with different size, which significantly affect the margination of particles. [178a,180] Moreover, blood composition is highly complex and blood cells can significantly affect the margination behavior of particles.…”