title: 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.
authors.affiliation: Institute for Drug Research, The Hebrew University of Jerusalem, Jerusalem, Israel.
authors.forename: Efrat
authors.initials: E
authors.lastname: Harel
authors.forename: Abraham
authors.initials: A
authors.lastname: Rubinstein
authors.forename: Aviram
authors.initials: A
authors.lastname: Nissan
authors.forename: Elena
authors.initials: E
authors.lastname: Khazanov
authors.forename: Mirela
authors.initials: M
authors.lastname: Nadler Milbauer
authors.forename: Yechezkel
authors.initials: Y
authors.lastname: Barenholz
authors.forename: Boaz
authors.initials: B
authors.lastname: Tirosh
mesh_terms: D000818:Animals; D000906:Antibodies / Q000737:chemistry / Q000276:immunology; D015153:Blotting, Western; D018938:Caco-2 Cells; D049109:Cell Proliferation / Q000187:drug effects; D003092:Colitis / Q000378:metabolism; D003106:Colon / Q000166:cytology*; D016207:Cytokines / Q000494:pharmacology*; D020895:Enterocytes / Q000187:drug effects* / Q000378:metabolism*; D005434:Flow Cytometry; D006801:Humans; D066298:In Vitro Techniques; D015212:Inflammatory Bowel Diseases / Q000235:genetics / Q000378:metabolism; D008081:Liposomes / Q000737:chemistry / Q000378:metabolism; D008297:Male; D051379:Mice; D051381:Rats; D011990:Receptors, Transferrin / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D000906:Antibodies; D016207:Cytokines; D008081:Liposomes; D011990:Receptors, Transferrin; D014409:Tumor Necrosis Factor-alpha