Tight Junction Modulating Bioprobes for Drug Delivery System to the Brain: A Review

Abstract

The blood-brain barrier (BBB), which is composed of endothelial cells, pericytes, astrocytes, and neurons, separates the brain extracellular fluid from the circulating blood, and maintains the homeostasis of the central nervous system (CNS). The BBB endothelial cells have well-developed tight junctions (TJs) and express specific polarized transport systems to tightly control the paracellular movements of solutes, ions, and water. There are two types of TJs: bicellular TJs (bTJs), which is a structure at the contact of two cells, and tricellular TJs (tTJs), which is a structure at the contact of three cells. Claudin-5 and angulin-1 are important components of bTJs and tTJs in the brain, respectively. Here, we review TJ-modulating bioprobes that enable drug delivery to the brain across the BBB, focusing on claudin-5 and angulin-1.

Blood–Brain Barrier in Brain Tumors: Biology and Clinical Relevance

“…Claudin-5 and angulin-1 are considered candidate targets for drug delivery through the BBB [ 68 ]. Clostridium perfringens enterotoxin (CPE) can bind with high affinity to claudin-3 and claudin-4, modulating the function of the epithelial TJ barrier [ 69 ].…”

“…Another claudin-5 modulator is polyinosinic-polycytidylic acid (poly IC), a ligand of toll-like receptor 3 (TLR3), which reduces the expression of claudin-5 in a dose and time-dependent manner [ 70 ]. Bevacizumab, an antiangiogenetic agent, downregulates claudin-5 by upregulation of TGFβ1 (transforming growth factor β1) [ 68 ]. Fragments of bacterial toxins (clostridium perfringens iota-toxin) and antibodies against Angulin-1 can increase the permeability of BBB as well [ 71 ].…”

Development, Structure, and Mechanism of Synthetic Antibodies that Target Claudin and Clostridium perfringens Enterotoxin Complexes

“…The process of b-pore formation disables claudin/claudin interactions vital to TJ assembly and ultimately dissociates TJs causing paracellular leakage prior to CpEinduced cell death. Crystal structures of cCpE bound to receptor claudins have shed light on their interprotein interactions and have helped to inform structure-guided design of modified cCpEs used to detect or destroy cancer cells or to modulate the blood-brain barrier for drug delivery (19)(20)(21)(22)(23)(24)(25)(26)(27). Yet, a complete structural and mechanistic understanding of CpE dissociation of TJs and the process of cytotoxic b-pore formation remains elusive.…”

Characterizing the Contributions of Various Clostridium perfringens Enterotoxin Properties to In Vivo and In Vitro Permeability Effects

“…CPE or its derivatives have been explored for use in cancer therapy, imaging, or diagnosis ( 27 ). These proteins are also being explored for use as mucosal adjuvants and for drug delivery across a mucosal epithelium ( 28 – 33 ).…”