CHOLESTEROL LOADED NANOPARTICLES INJECTED SYSTEMICALLY REACH THE BRAIN AND LOCALIZE INTO SPECIFIC CELL TYPES

Changes in brain cholesterol biosynthesis have been reported in Huntington’s disease (HD) (Valenza et al., J. Neurosci. 2005; Valenza et al., J. Neurosci. 2010). In particular, biochemical and mass spectrometry analyses showed reduced levels of several cholesterol precursors in brain of multiple HD rodent models, leading to reduced content of sterols/cholesterol (Valenza et al., Hum Mol Genet. 2007; Valenza et al., J. Neurosci. 2010). Other authors have reported accumulation of sterols in HD brains and cell models, as measured by methods other than Mass Spectrometry (Trushina et al., Hum Mol genet. 2006; LuthiCarter et al., PNAS 2010; DelToro et al., J Neurochem. 2010), questioning whether decreased cholesterol biosynthesis in HD is a primary event leading to reduced content of sterols or a consequence of sterol accumulation. To test the impact of changes in cholesterol levels in HD brain, we injected systemically cholesterol loaded poly-lactide-co-glycolide (PLGA) Nanoparticles (Nps) modified with glycopeptides (M-Nps) to obtain high rate brain delivery (Tosi et al., Expert Opin Drug Deliv. 2008 ). Differently from unmodified Nps (C-Nps), we show that M-Nps loaded with cholesterol (M-Nps-chol) efficiently enter the brain, and localize in different brain cells within 4 hrs after i.p. injection while persisting for several weeks both in wt and HD (R6/2) mice. Additionally, a pilot study suggests that multiple injections of M-Nps-chol in R6/2 mice positively influence some electrophysiological parameters compared to animals that received empty M-Nps. These preliminary findings suggest that M-Nps may represent a novel route to deliver molecules (besides cholesterol) in the brain and that cholesterol released by M-Nps may modulate functional parameters in vivo. Further studies toward this direction will be critical for defining the impact of a cholesterol defect in HD pathogenesis and its possible efficacy from a therapeutical standpoint.