Intracerebral Nanoparticle Transport Facilitated by Alzheimer Pathology and Age

Nano Lett. 2023 Dec 13;23(23):10971-10982. doi: 10.1021/acs.nanolett.3c03222. Epub 2023 Nov 22.

Abstract

Nanoparticles have emerged as potential transporters of drugs targeting Alzheimer's disease (AD), but their design should consider the blood-brain barrier (BBB) integrity and neuroinflammation of the AD brain. This study presents that aging is a significant factor for the brain localization and retention of nanoparticles, which we engineered to bind with reactive astrocytes and activated microglia. We assembled 200 nm-diameter particles using a block copolymer of poly(lactic-co-glycolic acid) (PLGA) and CD44-binding hyaluronic acid (HA). The resulting PLGA-b-HA nanoparticles displayed increased binding to CD44-expressing reactive astrocytes and activated microglia. Upon intravascular injection, nanoparticles were localized to the hippocampi of both APP/PS1 AD model mice and their control littermates at 13-16 months of age due to enhanced transvascular transport through the leaky BBB. No particles were found in the hippocampi of young adult mice. These findings demonstrate the brain localization of nanoparticles due to aging-induced BBB breakdown regardless of AD pathology.

Keywords: Alzheimer’s disease; PLGA nanoparticles; aging; blood-brain barrier; hyaluronic acid; reactive astrocytes.

MeSH terms

  • Alzheimer Disease* / metabolism
  • Animals
  • Blood-Brain Barrier / metabolism
  • Brain / metabolism
  • Mice
  • Mice, Transgenic
  • Nanoparticles*
  • Polylactic Acid-Polyglycolic Acid Copolymer / metabolism

Substances

  • Polylactic Acid-Polyglycolic Acid Copolymer