Effect of size, surface charge, and hydrophobicity on the translocation of polystyrene microspheres through gastrointestinal mucin

Abstract

Microspheres (MS) have been proposed for use as oral vaccine delivery vehicles (VDV); however, due to poor and variable absorption their clinical utility is limited. The effects of size, z-potential, and surface hydrophobicity on the translocation (P T ) permeabilities of polystyrene (PS) MS with varying surface functional groups (amidine, carboxyl, carboxylate-modified [CML], and sulfate) were determined through gastrointestinal (GI) mucin. P T were determined, under steady-state conditions, using a modified Ussing-type diffusion chamber and a mucin packet developed for use with the Transwell-Snapwell system. P T followed the Stokes-Einstein relationship, demonstrating the limited ability of larger MS ( ú0.5 mm) to diffuse through the mucin layer. P T also varied according to the surface characteristics. Even though the z-potential did not correlate with the transport of MS through mucin, surface ionization appears to be important in MS translocation. The PS-amidine MS were significantly less hydrophobic and had a higher P T than that of the other MS, suggesting that hydrophobicity is also a significant factor in MS transport through mucin. While these results suggest that mucin may be a significant barrier to the oral absorption of vaccines and VDVs in vivo, the rate-limiting barrier for the absorption of MS will be the intestinal mucosa.

Rapid transport of large polymeric nanoparticles in fresh undiluted human mucus

“…An important role of mucus barriers is to trap foreign particles and then clear them from the body before they reach the underlying epithelia (24,31). The mucus barrier has been cited as a critical bottleneck in the treatment of a variety of diseases (17,24,(31)(32)(33)(34), and it has been widely suggested that nanoparticles are unable to efficiently traverse mucus layers (35)(36)(37)(38)(39), including CV mucus (27). For applications in CV diseases, the need for improved particle transport is further underscored by: (i) the previous observation that polystyrene beads firmly adhere to mucin fibers in human CV secretions, rendering them completely immobile (27); (ii) there is 100-to 1,000-fold reduced D eff for herpes simplex virus (d ϭ 180 nm) in CV mucus compared with water (27); and (iii) there are existing estimates of CV mucus mesh pore size of 10 to at most 200 nm from fluorescence recovery after photobleaching (FRAP) and most electron microscopy studies (27,28).…”

“…The transport of hydrophobic polystyrene particles without PEG modification was characterized by significant entrapment within and adhesion to the mucosal network, presumably because of the hydrophobic polystyrene bead-forming polyvalent bonds with hydrophobic domains distributed along mucin fibers (27,35). However, it was not obvious, a priori, that PEG may reduce association of particles with mucus components, because high-molecular mass PEG (Ͼ10 kDa) has been shown to exhibit mucoadhesive properties involving interpenetration of the polymer with mucus fibers (58).…”

“…A number of reports have examined particle size and transport or cellular uptake in mucosal environments; however, none has reported observations of smaller particles moving more slowly than larger particles (35)(36)(37)(38)(39). The majority of studies compared particle sizes spanning orders of magnitude and concluded that smaller particles move faster (36)(37)(38).…”

Methods to determine the interactions of micro- and nanoparticles with mucus

“…However, the central compartment of the Transwell-Snapwell system containing the vertical mucus layer is separated from the donor and the acceptor compartment by filters [28]. Due to the separation of the mucus layer from the donor chamber the Transwell Snapwell diffusion system has an additional barrier for particles compared to the human gastrointestinal passage.…”

“…Norris et al adapted the Ussing chamber system with Snapwell rings and filters obtaining a vertical layer for mucus between the donor and acceptor chambers as is illustrated in Fig. 2 [28]. The three compartment diffusion system is thereby based on a donor and acceptor compartment separated by a central compartment containing a vertical layer of mucus.…”