TY - JOUR
T1 - Insights into kinetics, release, and behavioral effects of brain-targeted hybrid nanoparticles for cholesterol delivery in Huntington's disease
AU - Birolini, Giulia
AU - Valenza, Marta
AU - Ottonelli, Ilaria
AU - Passoni, Alice
AU - Favagrossa, Monica
AU - Duskey, Jason T
AU - Bombaci, Mauro
AU - Vandelli, Maria Angela
AU - Colombo, Laura
AU - Bagnati, Renzo
AU - Caccia, Claudio
AU - Leoni, Valerio
AU - Taroni, Franco
AU - Forni, Flavio
AU - Ruozi, Barbara
AU - Salmona, Mario
AU - Tosi, Giovanni
AU - Cattaneo, Elena
N1 - Copyright © 2021 Elsevier B.V. All rights reserved.
PY - 2021/2/10
Y1 - 2021/2/10
N2 - Supplementing brain cholesterol is emerging as a potential treatment for Huntington's disease (HD), a genetic neurodegenerative disorder characterized, among other abnormalities, by inefficient brain cholesterol biosynthesis. However, delivering cholesterol to the brain is challenging due to the blood-brain barrier (BBB), which prevents it from reaching the striatum, especially, with therapeutically relevant doses. Here we describe the distribution, kinetics, release, and safety of novel hybrid polymeric nanoparticles made of PLGA and cholesterol which were modified with an heptapeptide (g7) for BBB transit (hybrid-g7-NPs-chol). We show that these NPs rapidly reach the brain and target neural cells. Moreover, deuterium-labeled cholesterol from hybrid-g7-NPs-chol is released in a controlled manner within the brain and accumulates over time, while being rapidly removed from peripheral tissues and plasma. We confirm that systemic and repeated injections of the new hybrid-g7-NPs-chol enhanced endogenous cholesterol biosynthesis, prevented cognitive decline, and ameliorated motor defects in HD animals, without any inflammatory reaction. In summary, this study provides insights about the benefits and safety of cholesterol delivery through advanced brain-permeable nanoparticles for HD treatment.
AB - Supplementing brain cholesterol is emerging as a potential treatment for Huntington's disease (HD), a genetic neurodegenerative disorder characterized, among other abnormalities, by inefficient brain cholesterol biosynthesis. However, delivering cholesterol to the brain is challenging due to the blood-brain barrier (BBB), which prevents it from reaching the striatum, especially, with therapeutically relevant doses. Here we describe the distribution, kinetics, release, and safety of novel hybrid polymeric nanoparticles made of PLGA and cholesterol which were modified with an heptapeptide (g7) for BBB transit (hybrid-g7-NPs-chol). We show that these NPs rapidly reach the brain and target neural cells. Moreover, deuterium-labeled cholesterol from hybrid-g7-NPs-chol is released in a controlled manner within the brain and accumulates over time, while being rapidly removed from peripheral tissues and plasma. We confirm that systemic and repeated injections of the new hybrid-g7-NPs-chol enhanced endogenous cholesterol biosynthesis, prevented cognitive decline, and ameliorated motor defects in HD animals, without any inflammatory reaction. In summary, this study provides insights about the benefits and safety of cholesterol delivery through advanced brain-permeable nanoparticles for HD treatment.
KW - Animals
KW - Brain
KW - Cholesterol
KW - Huntington Disease/drug therapy
KW - Kinetics
KW - Nanoparticles
U2 - 10.1016/j.jconrel.2020.12.051
DO - 10.1016/j.jconrel.2020.12.051
M3 - Article
C2 - 33412229
VL - 330
SP - 587
EP - 598
JO - Journal of Controlled Release
JF - Journal of Controlled Release
SN - 0168-3659
ER -