Claudin-1-Targeted Nanoparticles for Delivery to Aging-Induced Alterations in the Blood-Brain Barrier.
Badrul Alam BonyAria W TarudjiHunter A MillerSaiprasad GowrikumarSourav RoyEvan T CurtisConnor C GeeAlex VecchioPunita DhawanForrest M KievitPublished in: ACS nano (2021)
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.
Keyphrases
- blood brain barrier
- cognitive decline
- poor prognosis
- high glucose
- magnetic resonance imaging
- endothelial cells
- fluorescence imaging
- binding protein
- cerebral ischemia
- resting state
- white matter
- diabetic rats
- multiple sclerosis
- functional connectivity
- computed tomography
- small molecule
- cancer therapy
- mild cognitive impairment
- high fat diet induced
- drug induced
- oxidative stress
- photodynamic therapy
- type diabetes
- long non coding rna
- insulin resistance
- skeletal muscle
- metabolic syndrome
- brain injury
- vascular endothelial growth factor
- cross sectional
- magnetic resonance
- high resolution
- mass spectrometry
- diffusion weighted imaging