Focused ultrasound on the substantia nigra enables safe neurotensin-polyplex nanoparticle-mediated gene delivery to dopaminergic neurons intranasally and by blood circulation.
Bionanotechnology
Gene transfection
Motor behavior
Nanomedicine
Parkinson’s disease
Reversible neurodegeneration
Transient neuroinflammation
Journal
Discover nano
ISSN: 2731-9229
Titre abrégé: Discov Nano
Pays: Switzerland
ID NLM: 9918540788706676
Informations de publication
Date de publication:
02 Apr 2024
02 Apr 2024
Historique:
received:
18
12
2023
accepted:
27
03
2024
medline:
2
4
2024
pubmed:
2
4
2024
entrez:
2
4
2024
Statut:
epublish
Résumé
Neurotensin-polyplex nanoparticles provide efficient gene transfection of nigral dopaminergic neurons when intracerebrally injected in preclinical trials of Parkinson's disease because they do not cross the blood-brain barrier (BBB). Therefore, this study aimed to open BBB with focused ultrasound (FUS) on the substantia nigra to attain systemic and intranasal transfections and evaluate its detrimental effect in rats. Systemically injected Evans Blue showed that a two-pulse FUS opened the nigral BBB. Accordingly, 35 μL of neurotensin-polyplex nanoparticles encompassing the green fluorescent protein plasmid (79.6 nm mean size and + 1.3 mV Zeta-potential) caused its expression in tyrosine hydroxylase(+) cells (dopaminergic neurons) of both substantiae nigrae upon delivery via internal carotid artery, retro-orbital venous sinus, or nasal mucosa 30 min after FUS. The intracarotid delivery yielded the highest transgene expression, followed by intranasal and venous administration. However, FUS caused neuroinflammation displayed by infiltrated lymphocytes (positive to cluster of differentiation 45), activated microglia (positive to ionized calcium-binding adaptor molecule 1), neurotoxic A1 astrocytes (positive to glial fibrillary acidic protein and complement component 3), and neurotrophic A2 astrocytes (positive to glial fibrillary acidic protein and S100 calcium-binding protein A10), that ended 15 days after FUS. Dopaminergic neurons and axonal projections decreased but recuperated basal values on day 15 after transfection, correlating with a decrease and recovery of locomotor behavior. In conclusion, FUS caused transient neuroinflammation and reversible neuronal affection but allowed systemic and intranasal transfection of dopaminergic neurons in both substantiae nigrae. Therefore, FUS could advance neurotensin-polyplex nanotechnology to clinical trials for Parkinson's disease.
Identifiants
pubmed: 38564106
doi: 10.1186/s11671-024-04005-9
pii: 10.1186/s11671-024-04005-9
doi:
Types de publication
Journal Article
Langues
eng
Pagination
60Subventions
Organisme : CONAHCYT
ID : 254686
Informations de copyright
© 2024. The Author(s).
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