Enhanced Transferrin Receptor Expression by Proinflammatory Cytokines in Enterocytes as a Means for Local Delivery of Drugs to Inflamed Gut Mucosa

Abstract

Therapeutic intervention in inflammatory bowel diseases (IBDs) is often associated with adverse effects related to drug distribution into non-diseased tissues, a situation which attracts a rational design of a targeted treatment confined to the inflamed mucosa. Upon activation of immune cells, transferrin receptor (TfR) expression increases at their surface. Because TfR is expressed in all cell types we hypothesized that its cell surface levels are regulated also in enterocytes. We, therefore, compared TfR expression in healthy and inflamed human colonic mucosa, as well as healthy and inflamed colonic mucosa of the DNBS-induced rat model. TfR expression was elevated in the colonic mucosa of IBD patients in both the basolateral and apical membranes of the enterocytes. Increased TfR expression was also observed in colonocytes of the induced colitis rats. To explore the underlying mechanism CaCo-2 cells were treated with various proinflammatory cytokines, which increased both TfR expression and transferrin cellular uptake in a mechanism that did not involve hyper proliferation. These findings were then exploited for the design of targetable carrier towards inflamed regions of the colon. Anti-TfR antibodies were conjugated to nano-liposomes. As expected, iron-starved Caco-2 cells internalized anti-TfR immunoliposomes better than controls. Ex vivo binding studies to inflamed mucosa showed that the anti-TfR immunoliposomes accumulated significantly better in the mucosa of DNBS-induced rats than the accumulation of non-specific immunoliposomes. It is concluded that targeting mucosal inflammation can be accomplished by nano-liposomes decorated with anti-TfR due to inflammation-dependent, apical, elevated expression of the receptor.

An inflammation-targeting hydrogel for local drug delivery in inflammatory bowel disease

“…Two hundred microliters of (DiD + Dex)–loaded 4% IT-hydrogel [(DiD + Dex)/gel] was suspended in 6 ml of PBS. The colon was inverted and incubated in 0.5 ml of gel suspension for 30 min at 37°C with gentle shaking (34). After washing with PBS (3×), the colon was opened longitudinally and imaged using an IVIS fluorescence imager (IVIS 200, PerkinElmer) with the luminal side facing up.…”

Advances in oral nano-delivery systems for colon targeted drug delivery in inflammatory bowel disease: Selective targeting to diseased versus healthy tissue

“…immune cells, including lymphocytes and macrophages(146) Harel et al (2011). investigated the ex vivo adhesion capacity of immunoliposomes with anti-TfR antibodies conjugated to its surface to inflamed mucosal tissue(147).…”

“…investigated the ex vivo adhesion capacity of immunoliposomes with anti-TfR antibodies conjugated to its surface to inflamed mucosal tissue(147). The study reported mucopenetration of the targeted formulation, with a 4-fold increase in uptake in inflamed colon tissue from the TNBS-induced colitis model, compared to non-inflamed colon tissue.…”

Application of liposomes in drug development – focus on gastroenterological targets

“…28 Transferrin (TF) and its receptor (TfR) were shown to be overexpressed in inflamed colonic mucosa. 29,30 Tirosh et al reported that negatively charged liposomes bound to TF in an acidic environment of inflamed colon mucosa 29 and anti-TfR antibody conjugated liposomes significantly improve the accumulation of immunoliposome in the mucosa of dinitrobenzensulfonic acid (DNBS) induced rat, 30 which provides a target and potential drug delivery strategy to treat UC.…”