Influence of particle size and shape on their margination and wall-adhesion: implications in drug delivery vehicle design across nano-to-micro scale

Abstract

Intravascular drug delivery technologies majorly utilize spherical nanoparticles as carrier vehicles. Their targets are often at the blood vessel wall or in the tissue beyond the wall, such that vehicle localization towards the wall (margination) becomes a pre-requisite for their function. To this end, some studies have indicated that under flow environment, micro-particles have a higher propensity than nano-particles to marginate to the wall. Also, non-spherical particles theoretically have a higher area of surface-adhesive interactions than spherical particles. However, detailed systematic studies that integrate various particle size and shape parameters across nano-to-micro scale to explore their wall-localization behavior in RBC-rich blood flow, have not been reported. We address this gap by carrying out computational and experimental studies utilizing particles of four distinct shapes (spherical, oblate, prolate, rod) spanning nano- to-micro scale sizes. Computational studies were performed using the Large-scale Atomic/Molecular Massively Parallel Simulator (LAMMPS) package, with Dissipative Particle Dynamics (DPD). For experimental studies, model particles were made from neutrally buoyant fluorescent polystyrene spheres, that were thermo-stretched into non-spherical shapes and all particles were surface-coated with biotin. Using microfluidic setup, the biotin-coated particles were flowed over avidin-coated surfaces in absence versus presence of RBCs, and particle adhesion and retention at the surface was assessed by inverted fluorescence microscopy. Our computational and experimental studies provide a simultaneous analysis of different particle sizes and shapes for their retention in blood flow and indicate that in presence of RBCs, micro-scale non-spherical particles undergo enhanced 'margination + adhesion' compared to nano-scale spherical particles, resulting in their higher binding. These results provide important insight regarding improved design of vascularly targeted drug delivery systems.

Size, shape, and flexibility influence nanoparticle transport across brain endothelium under flow

“…The effect of particle size on adhesion to cellular or synthetic surfaces under flow has been investigated in quite some depth . These studies have been generally performed with micron‐sized particles, thereby limiting comparisons to the present study.…”

“…These studies have been generally performed with micron‐sized particles, thereby limiting comparisons to the present study. In one study, adhesion of spherical particles to surfaces under flow was reported and the dependence of adhesion on size was nonmonotonic with 500 nm particles exhibiting maximum adhesion compared to 100 nm, 200 nm, and 2 μm particles . Mathematical models have also been reported to describe wall adhesion of particles under flow.…”

“…The appeal of nanoparticles lies in their ability to offer benefits such as extended drug circulation times, protection of drugs from degradation, controlled drug release, improved drug targeting, and potential to respond to external stimuli . As more advanced nanoparticles are developed for therapeutic applications, the extent to which their biological performance can be improved by altering the physical or chemical properties has received significant attention . The impact of modulating physical properties such as size, shape, flexibility, or charge is especially important to consider because these are some of the most fundamental nanoparticle attributes and can be tuned to improve performance.…”

A unified analysis of nano-to-microscale particle dispersion in tubular blood flow

“…Consequently, questions such as whether nanoscale particles exhibit margination qualitatively the same as microscale particle does still remains controversial. A recent effort by Cooley et al 30 using in vitro experiment and 2D in silico simulation to understand the cross-length-scale particle margination and adhesion propensity has set an example for a unified understanding of the nano-to-microscale particle dispersion in blood flows. However, the general physical mechanisms behind the multiscale particle dispersion/margination phenomenon in blood are still not presented; besides, the 2D simulation could still overlook the 3D nature of the tubular blood flow phenomena.…”

Fabrication, Characterization, and in Vitro Evaluation of Pegylated Glyceride Labrasol® Nanostructured Lipid Carrier Composites of Methotrexate: The Pathway to Effective Cancer Therapy

“…cancer targeting, PS ranging from 100 to 300 nm is considered to be suitable as these particles can easily penetrate into the intracellular space [43]. Due to the presence of PEG chains at the surface of the nanoparticles, the outer layer of Labrasol ® MTX-NLC is slightly lighter in color in comparison to olive oil MTX-NLC [44].…”