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J Control Release. 2017 Aug 28;260:1-11. doi: 10.1016/j.jconrel.2017.05.024. Epub 2017 May 18.

Angubindin-1, a novel paracellular absorption enhancer acting at the tricellular tight junction.

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Institute of Clinical Physiology, Department of Gastroenterology, Rheumatology and Infectious Diseases, Campus Benjamin Franklin, Charité - Universitätsmedizin Berlin, 12203 Berlin, Germany.
Graduate School of Pharmaceutical Sciences, Osaka University, Osaka 565-0871, Japan.
Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Tokushima 770-8514, Japan.
Proteo-Science Center, Ehime University, Ehime 790-8577, Japan.
Graduate School of Pharmaceutical Sciences, Osaka University, Osaka 565-0871, Japan. Electronic address:


A limiting barrier for mucosal absorption of drugs is the tight junction (TJ). TJs exist between two adjacent cells (bicellular TJ, bTJ) and at the sites where three cells meet (tricellular TJ, tTJ). We present a novel approach which employs a physiologically regulated pathway for the passage of large molecules through the tTJ. Main barrier-relevant tTJ proteins are tricellulin and angulin-1 to -3. We developed an angulin binder from Clostridium perfringens iota-toxin (Ib) whose receptor is angulin-1. An Ib fragment corresponding to amino acids 421-664 (Ib421-664) of iota-toxin proved to bind in cells expressing angulin-1 and -3, but not angulin-2. This binding led to removal of angulin-1 and tricellulin from the tTJ which enhanced the permeation of macromolecular solutes. Ib421-664 enhanced intestinal absorption in rats and mice. Our findings indicate that Ib421-664, which we designate angubindin-1, is a modulator of the tTJ barrier and that modulation of that barrier qualifies for a new strategy of developing a mucosal absorption enhancer.


Absorption enhancer; Mucosal absorption; Paracellular passage; Tight junction

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