(331e) Targeting Dysfunctional Blood-Brain Barrier Improves Nanoparticle Delivery into the Brain

Brain delivery of therapeutics is significantly hindered by the blood-brain barrier (BBB) that prevents the passive accumulation of materials in the brain. Nanoparticle (NP) delivery systems have been shown to improve brain accumulation and retention when there is severe disruption of the BBB such as in traumatic brain injury or brain cancer. However, delivery is still limited in disease states where BBB disruption is much less severe such as concussion and progressive neurodegenerative diseases observed during aging. Recent evidence suggests the tight junction protein claudin-1, which is not expressed in normally functioning brain endothelium, is increased on the brain endothelium during disease. Therefore, we hypothesized that targeting claudin-1 would allow for increased brain delivery specifically within dysfunctional regions of the BBB. PEG coated ultrasmall (3.5 nm) gadolinium NPs were modified with the claudin-1-targeting peptide C1C2. These NPs had approximately 19 peptides per NP with a coating density of around 1 peptide per 2 nm² of NP surface area. We found increased NP accumulation in brains of 12-month-old mice (corresponding to middle age in humans) as compared to 2-month-old mice as determined through MRI and confocal imaging. This increased accumulation correlated with increased expression of claudin-1 on brain endothelial cells in the 12-month-old mice. Additionally, we observed increased accumulation of these claudin-1-targeted NPs following traumatic brain injury, which correlated with increased claudin-1 expression. Our results strongly suggest claudin-1 as a strong target for improving delivery of nanoparticle-based therapeutics into the brain when severe disruption of the BBB is not present.