Effect of surface chemistry on nanoparticle interaction with gastrointestinal mucus and distribution in the gastrointestinal tract following oral and rectal administration in the mouse

Abstract

It is believed that mucoadhesive surface properties on particles delivered to the gastrointestinal (GI) tract improve oral absorption or local targeting of various difficult-to-deliver drug classes. To test the effect of nanoparticle mucoadhesion on distribution of nanoparticles in the GI tract, we orally and rectally administered nano- and microparticles that we confirmed possessed surfaces that were either strongly mucoadhesive or non-mucoadhesive. We found that mucoadhesive particles (MAP) aggregated in mucus in the center of the GI lumen, far away from the absorptive epithelium, both in healthy mice and in a mouse model of ulcerative colitis (UC). In striking contrast, water absorption by the GI tract rapidly and uniformly transported non-mucoadhesive mucus-penetrating particles (MPP) to epithelial surfaces, including reaching the surfaces between villi in the small intestine. When using high gavage fluid volumes or injection into ligated intestinal loops, common methods for assessing oral drug and nanoparticle absorption, we found that both MAP and MPP became well-distributed throughout the intestine, indicating that the barrier properties of GI mucus were compromised. In the mouse colorectum, MPP penetrated into mucus in the deeply in-folded surfaces to evenly coat the entire epithelial surface. Moreover, in a mouse model of UC, MPP were transported preferentially into the disrupted, ulcerated tissue. Our results suggest that delivering drugs in non-mucoadhesive MPP is likely to provide enhanced particle distribution, and thus drug delivery, in the GI tract, including to ulcerated tissues.

Enema ion compositions for enhancing colorectal drug delivery

“…However, drugs or drug-loaded nanoparticles must pass through the “filter” formed by highly viscoelastic and adhesive layers of mucus coating the GI tract epithelium, or be trapped and rapidly cleared along with the ‘sloppy’ layers of mucus farthest from the epithelium [9, 10]. We previously found that nanoparticles sufficiently small and well-coated to slip through the mucus barrier, mucus-penetrating particles (MPP), can be efficiently delivered to the entire colorectal epithelial surface [11-14]. Rapid and widespread distribution of MPP was driven by the rapid absorption of water from hypotonic solution “advectively” transporting MPP to the epithelium much faster than by diffusion alone [11].…”

“…We previously found that nanoparticles sufficiently small and well-coated to slip through the mucus barrier, mucus-penetrating particles (MPP), can be efficiently delivered to the entire colorectal epithelial surface [11-14]. Rapid and widespread distribution of MPP was driven by the rapid absorption of water from hypotonic solution “advectively” transporting MPP to the epithelium much faster than by diffusion alone [11]. Similarly, we found that hypotonic vehicles induced fluid absorption by the vaginal epithelium that rapidly delivered water-soluble drugs and MPP to the epithelial surface by advection [15, 16].…”

Surface charge effect on mucoadhesion of chitosan based nanogels for local anti-colorectal cancer drug delivery

“…The targeted therapy effect is achieved through preventing the drug release in stomach and triggering release at the target site [8,11]. The specific surface characteristics of nanocarriers can increase the contact between loaded drug and intestinal mucosa and enhance cellular uptake of formulation [3,12,13]. High local drug concentration is created in lesion, resulting in high mortality of cancer cell, which is beneficial to decrease the required dosage and frequency of administration, reduced toxicity and cost [14,15].…”

Nanotherapeutics for the treatment of inflammatory bowel disease

“…It is generally accepted that mucus-penetrating NPs, characterized by size less than the mucus mesh spacing and non-mucoadhesive surface, preferentially penetrate the mucus layer deeply. In contrast, the mucoadhesive NPs tend to stick to mucus components and aggregate locally [14].…”