Insights into kinetics, release, and behavioral effects of brain-targeted hybrid nanoparticles for cholesterol delivery in Huntington's disease

Giulia Birolini, Marta Valenza, Ilaria Ottonelli, Alice Passoni, Monica Favagrossa, Jason T Duskey, Mauro Bombaci, Maria Angela Vandelli, Laura Colombo, Renzo Bagnati, Claudio Caccia, Valerio Leoni, Franco Taroni, Flavio Forni, Barbara Ruozi, Mario Salmona, Giovanni Tosi, Elena Cattaneo

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)587-598
Number of pages12
JournalJournal of Controlled Release
Volume330
DOIs
Publication statusPublished - Feb 10 2021

Keywords

  • Animals
  • Brain
  • Cholesterol
  • Huntington Disease/drug therapy
  • Kinetics
  • Nanoparticles

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