Tight junction modulation of the blood brain barrier: CNS delivery of small molecules.
Authors: Greene C, Campbell M
The blood brain barrier (BBB) represents a major obstacle for targeted drug delivery to the brain for the treatment of central nervous system (CNS) disorders. Significant advances in barrier research over the past decade has led to the discovery of an increasing number of structural and regulatory proteins in tight junctions (TJ) and adherens junctions (AJ). These discoveries are providing the framework for the development of novel TJ modulators which can act specifically and temporarily to alter BBB function and regulate paracellular uptake of molecules. TJ modulators that have shown therapeutic potential in preclinical models include claudin-5 and occludin siRNAs, peptides derived from zonula occludens toxin as well as synthetic peptides targeting the extracellular loops of TJs. Adding to the array of modulating agents are novel mechanisms of BBB regulation such as focused ultrasound (FUS). This review will give a succinct overview of BBB biology and TJ modulation in general. Novel insights into BBB regulation in health and disease will also be summarized.
Introduction
Purpose
Drug delivery with BBB opening
Study Objective
To provide a succinct overview of blood–brain barrier biology and tight junction modulation and to summarize novel insights into BBB regulation in health and disease.
Animal model / Human subject
Not specified in the provided text
Disease model
central nervous system disorders (blood-brain barrier modulation)
MRI or image guidance method
Not specified in the provided text.
Targeted brain region(s)
Not Specified
Target coordinates
not reported
Cargo name and characteristics
siRNAs targeting claudin-5 and occludin (nucleic acid therapeutics, gene‑silencing agents to reduce tight junction proteins); peptides derived from zonula occludens toxin (ZOT) and synthetic peptides targeting extracellular loops of tight junction proteins (peptide modulators that transiently disrupt TJ integrity); focused ultrasound (FUS) — a physical BBB modulation technique (non‑molecular, transiently increases paracellular permeability).
Route of administration
Not specified; delivery was achieved by transiently modulating the blood–brain barrier using tight-junction modulators (claudin-5 and occludin siRNAs, zonula occludens toxin-derived peptides, synthetic TJ-targeting peptides) and by focused ultrasound (FUS)
Outcomes and Safety
Summary of Outcomes
Targeting tight junction proteins with siRNAs, peptides, and focused ultrasound transiently and specifically increases blood–brain barrier permeability to enhance paracellular delivery of therapeutic molecules.
Duration of biological effect
not specified
Safety-related matter
No safety concerns or adverse effects are mentioned in the provided text.
Brain Region
Ultrasound Parameters
Ultrasound instrument
Not specified in text
FUS Frequency
Not specified
FUS Intensity
Not reported
FUS Pressure
Not reported
FUS Mode
not specified in the provided text
Pulse duration
Not reported
Duration of a single FUS session
Not specified in the provided text.
Focal Characteristics
High-level review: broad overview of BBB biology and tight junction modulation
Treatment frequency
Not specified
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