Diffusion of Particles in the Extracellular Matrix: The Effect of Repulsive Electrostatic Interactions

Abstract

Diffusive transport of macromolecules and nanoparticles in charged fibrous media is of interest in many biological applications, including drug delivery and separation processes. Experimental findings have shown that diffusion can be significantly hindered by electrostatic interactions between the diffusing particle and charged components of the extracellular matrix. The implications, however, have not been analyzed rigorously. Here, we present a mathematical framework to study the effect of charge on the diffusive transport of macromolecules and nanoparticles in the extracellular matrix of biological tissues. The model takes into account steric, hydrodynamic, and electrostatic interactions. We show that when the fiber size is comparable to the Debye length, electrostatic forces between the fibers and the particles result in slowed diffusion. However, as the fiber diameter increases the repulsive forces become less important. Our results explain the experimental observations that neutral particles diffuse faster than charged particles. Taken together, we conclude that optimal particles for delivery to tumors should be initially cationic to target the tumor vessels and then change to neutral charge after exiting the blood vessels.

Multistage nanoparticle delivery system for deep penetration into tumor tissue

“…In addition, a previous report suggested neutral particles are optimal for diffusion in the interstitial matrix (29). The ζ potential of the ≈100-nm QDGelNPs at pH 7.5 was −6.29 ± 0.22 mV and at pH 6 was −5.00 ± 0.12 mV.…”

“…By fitting the concentration profile of the cleaved QDGelNPs to a one-dimensional diffusion model (33,34), we obtained a diffusion coefficient of 2. (29,31). This result indicates that the diffusion coefficient of released QDs in dense collagen increases to that of ≈10 nm particles and any residual gelatin/glutaraldehyde fragments remaining on the surface do not impede their diffusion.…”

Tailoring nanoparticle designs to target cancer based on tumor pathophysiology

“…The degree of vascularization, cell density, and extracellular matrix (ECM) content of different-sized orthotopic human breast melanoma xenograft tumors derived from MDA-MB-435 cells in CD1 nude athymic mouse models were characterized. These parameters were selected because they have been shown to individually impact nanoparticle uptake rate, accumulation, and retention (20)(21)(22). Histological sections stained with CD31 antibodies were used to colorimetrically visualize tumor blood vessels, whereas Movat's Pentachrome staining was performed to highlight nuclei and ECM components such as proteoglycans, mucopolysaccharides, and collagen.…”

Intelligent drug delivery systems for the treatment of solid tumors

“…As far as the surface charge density of the particles is concerned, particles with a small cationic surface charge have superior transvascular flux compared to their anionic or neutral counterparts (19,20), but neutral particles are ideal for interstitial transport because they do not interact with negatively charged glycosaminoglycans (i.e. hyaluronic acid) or with collagen fibers that carry a slightly positive charge (21,22).…”