(175ah) Intracerebral Nanoparticle Transport Facilitated By Alzheimer Pathology and Age

The increasing incidence of Alzheimer's disease (AD) necessitates the development of innovative neurotherapeutic delivery systems capable of traversing the blood-brain barrier (BBB), a significant obstacle in treating neurological disorders. This study highlights how aging and AD pathology enhance the cerebral localization and retention of nanoparticles, focusing on their interaction with the AD-characteristic, CD44-expressing reactive astrocytes and activated microglia. By employing nanoparticles engineered to target these cells, we aimed to elucidate the mechanisms facilitating their enhanced penetration and persistence within the brain, particularly in the context of aging.

We synthesized nanoparticles with PLGA-b-HA, a block copolymer of poly(lactic-co-glycolic acid) (PLGA) and hyaluronic acid (HA), and examined their binding efficiency to CD44-positive cells and their cerebral distribution following intravascular administration in AD model mice and age-matched controls. Our findings reveal a preferential affinity of these nanoparticles for the targeted cells, demonstrating the targeting strategy's specificity. The investigation uniquely highlights that the augmentation of nanoparticle retention within the hippocampal region in aged mice is predominantly facilitated by alterations in BBB permeability related to aging, suggesting these nanoparticle-based delivery systems' applicability extends to a range of neurodegenerative disorders beyond AD.

In conclusion, this research recognizes aging as a crucial factor influencing the efficiency of nanoparticle transport across the BBB, independent of AD-specific pathology. These perspectives support a paradigm shift in the development of neurotherapeutic delivery systems, emphasizing the importance of considering age-associated BBB dynamics in devising treatments for neurodegenerative diseases.

This study was published in Nano Letters on Nov.22, 2023.

https://doi.org/10.1021/acs.nanolett.3c03222