Biodistribution and endocytosis of ICAM-1-targeting antibodies versus nanocarriers in the gastrointestinal tract in mice

Abstract

Drug delivery to the gastrointestinal (GI) tract is key for improving treatment of GI maladies, developing oral vaccines, and facilitating drug transport into circulation. However, delivery of formulations to the GI tract is hindered by pH changes, degradative enzymes, mucus, and peristalsis, leading to poor GI retention. Targeting may prolong residence of therapeutics in the GI tract and enhance their interaction with this tissue, improving such aspects. We evaluated nanocarrier (NC) and ligand-mediated targeting in the GI tract following gastric gavage in mice. We compared GI biodistribution, degradation, and endocytosis between control antibodies and antibodies targeting the cell surface determinant intercellular adhesion molecule 1 (ICAM-1), expressed on GI epithelium and other cell types. These antibodies were administered either as free entities or coated onto polymer NCs. Fluorescence and radioisotope tracing showed proximal accumulation, with preferential retention in the stomach, jejunum, and ileum; and minimal presence in the duodenum, cecum, and colon by 1 hour after administration. Upstream (gastric) retention was enhanced in NC formulations, with decreased downstream (jejunal) accumulation. Of the total dose delivered to the GI tract, ∼60% was susceptible to enzymatic (but not pHmediated) degradation, verified both in vitro and in vivo. Attenuation of peristalsis by sedation increased upstream retention (stomach, duodenum, and jejunum). Conversely, alkaline NaHCO 3 , which enhances GI transit by decreasing mucosal viscosity, favored downstream (ileal) passage. This suggests passive transit through the GI tract, governed by mucoadhesion and peristalsis. In contrast, both free anti-ICAM and anti-ICAM NCs demonstrated significantly enhanced upstream (stomach and duodenum) retention when compared to control IgG counterparts, suggesting GI targeting. This was validated by transmission electron microscopy and energy dispersive X-ray spectroscopy, which revealed anti-ICAM NCs in vesicular compartments within duodenal epithelial cells. These results will guide future work aimed at improving intraoral delivery of targeted therapeutics for the treatment of GI pathologies.

CD103 (αE Integrin) Undergoes Endosomal Trafficking in Human Dendritic Cells, but Does Not Mediate Epithelial Adhesion

“…Notably, all myeloid cells including DCs express β2 integrin (CD18). CD18 forms heterodimers with CD11a, CD11b, and CD11c (69) and contributes to cell-cell contact formation by binding to intracellular adhesion molecules (ICAMs), which may be expressed on gastric and intestinal epithelial cells (70, 71). Notably, adhesion of DCs to epithelial cells via β2 integrins would be consistent with our experimental observations that showed increased binding in the presence of Mn 2+ and decreased binding in the presence of EGTA.…”

Stimuli-Responsive Polymeric Nanosystem for Colon Specific Drug Delivery

“…Mane and Muro have investigated about this method and explained their experiment using anti-ICAM-antibodies which were surrounded over the nanoparticles. 52 On the oral administration of this antibody coated nanoparticle, it was found that after the exposure to enzymes present in GI tract, these antibodies were destructed while the nanoparticles got lodged in the duodenum. These scientists used techniques like transmission electron microscopy and energy dispersive X-ray in their experiments.…”

Significance of Ligand-Anchored Polymers for Drug Targeting in the Treatment of Colonic Disorders

“…Evaluation of benefit to risk ratio is very essential as ADRs may weaken the life quality related to health and may therefore prevent successful treatment of the disorder. To improvise therapeutic efficiency, and to reduce the adverse drug reactions, selective drug accumulation inside the colon at the inflamed sites can be done with the help of nanocarriers based delivery systems supplemented and coupled with active targeting approaches like ligands (Mane and Muro, 2012). An expanding number of ligands for targeted drug delivery are studied for drug approaches related to drug targeting specific for colon.…”

“…Moreover, it is discerned to reduce the adverse reactions, by further improving the selective drug accumulation at inflamed sites within the colon. While according to Mane and Muro (2012) the biodistribution and cellular uptake of polystyrene nanoparticles coated with anti-ICAM-1 antibodies was evaluated. According to Nayak et al (2018), the current status of drug delivery technologies was explored and highlighted.…”