Claudin-1-Targeted Nanoparticles for Delivery to Aging-Induced Alterations in the Blood–Brain Barrier

Abstract

Aging-induced alterations to the blood–brain barrier (BBB) are increasingly being seen as a primary event in chronic progressive neurological disorders that lead to cognitive decline. With the goal of increasing delivery into the brain in hopes of effectively treating these diseases, a large focus has been placed on developing BBB permeable materials. However, these strategies have suffered from a lack of specificity toward regions of disease progression. Here, we report on the development of a nanoparticle (C1C2-NP) that targets regions of increased claudin-1 expression that reduces BBB integrity. Using dynamic contrast enhanced magnetic resonance imaging, we find that C1C2-NP accumulation and retention is significantly increased in brains from 12 month-old mice as compared to nontargeted NPs and brains from 2 month-old mice. Furthermore, we find C1C2-NP accumulation in brain endothelial cells with high claudin-1 expression, suggesting target-specific binding of the NPs, which was validated through fluorescence imaging, in vitro testing, and biophysical analyses. Our results further suggest a role of claudin-1 in reducing BBB integrity during aging and show altered expression of claudin-1 can be actively targeted with NPs. These findings could help develop strategies for longitudinal monitoring of tight junction protein expression changes during aging as well as be used as a delivery strategy for site-specific delivery of therapeutics at these early stages of disease development.

How Nanoparticles Open the Paracellular Route of Biological Barriers: Mechanisms, Applications, and Prospects

“…The second approach involves cooperation with particular biomarkers overexpressed on various endothelial or epithelial cells. For instance, aging and injured BBB overexpressed claudin-1 more than health BBB; thus, peptide-modified claudin-1-targeted NPs could be mostly retained in injured brain microvascular endothelial cells and significantly boosted the drug delivery efficiency to the object region . The tumor-associated vascular and lymphatic endothelium significantly expressed membrane antigens, including endoglin, follicle-stimulating hormone receptor, and VEGFR2 .…”

“…ZO targeted peptide AT-1002 and claudin-1-targeted peptide C1C2 have been used to modify NPs, which is more targeted than NPs alone and opens the paracellular route more efficiently. 91,180 (ii) Peptides that target specific cells can be utilized to modify NPs. A CSK peptide, for example, has an affinity for goblet cells, the second largest colony of intestinal epithelial cells.…”

“…For instance, aging and injured BBB overexpressed claudin-1 more than health BBB; thus, peptide-modified claudin-1-targeted NPs could be mostly retained in injured brain microvascular endothelial cells and significantly boosted the drug delivery efficiency to the object region. 180 The tumorassociated vascular and lymphatic endothelium significantly expressed membrane antigens, including endoglin, 220 folliclestimulating hormone receptor, 221 and VEGFR2. 222 NPs like single-walled nanotubes, GO and Au-NPs modified with specific ligands can target antigens, which may locally modulate the opening of the tumor vascular endothelial barrier.…”

Need for a Paradigm Shift in the Treatment of Ischemic Stroke: The Blood-Brain Barrier

“…These new versatile NPs can simultaneously carry imaging agents (MRI or PET), therapeutic drugs, and targeting ligands to induce a controlled drug delivery that can be activated by internal (pH, temperature, redox) or external stimuli (light, temperature, magnetic field, ultrasound). Bony et al reported a new NP to monitor alterations in the TJ protein expression (claudin-1) that may cause BBB leakiness through non-invasive MR imaging as well as a targeted delivery vehicle to improve site-specific target engagement of delivered therapeutics in old mice [ 218 ]. As examples of internal and external stimuli, Yang et al showed a dual-targeted therapeutic strategy in vitro and in vivo reported to enable pH-sensitive drug release and that allows cerebral ischemia targeting to improve stroke therapeutic efficacy [ 219 ].…”

“…However, no efforts have been made on stroke prevention. The use of nanotechnology could facilitate access to the BBB [ 218 , 222 , 223 ] and open new and effective therapeutic targets to prevent the progression of chronic cerebral ischemia, the appearance of ischemic and haemorrhagic strokes, and cognitive deterioration associated with brain aging. To this end, further in vitro and in vivo studies should be developed in order to improve their applicability in clinical studies.…”