Rational development of fingolimod nano-embedded microparticles as nose-to-brain neuroprotective therapy for ischemic stroke.

Autor: Zhang X; Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, L2-08B, 2/F, Laboratory Block, 21 Sassoon Road, Pokfulam, Hong Kong SAR, China.; Advanced Biomedical Instrumentation Centre, Hong Kong Science Park, Shatin, Hong Kong SAR, China., Su G; Clinical Neuroscience Institute, The First Affiliated Hospital of Jinan University, Guangzhou, China., Shao Z; Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, L2-08B, 2/F, Laboratory Block, 21 Sassoon Road, Pokfulam, Hong Kong SAR, China.; Advanced Biomedical Instrumentation Centre, Hong Kong Science Park, Shatin, Hong Kong SAR, China., Chan HW; Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, L2-08B, 2/F, Laboratory Block, 21 Sassoon Road, Pokfulam, Hong Kong SAR, China., Li S; Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, L2-08B, 2/F, Laboratory Block, 21 Sassoon Road, Pokfulam, Hong Kong SAR, China.; Advanced Biomedical Instrumentation Centre, Hong Kong Science Park, Shatin, Hong Kong SAR, China., Chow S; Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, L2-08B, 2/F, Laboratory Block, 21 Sassoon Road, Pokfulam, Hong Kong SAR, China., Tsang CK; Clinical Neuroscience Institute, The First Affiliated Hospital of Jinan University, Guangzhou, China., Chow SF; Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, L2-08B, 2/F, Laboratory Block, 21 Sassoon Road, Pokfulam, Hong Kong SAR, China. asfchow@hku.hk.; Advanced Biomedical Instrumentation Centre, Hong Kong Science Park, Shatin, Hong Kong SAR, China. asfchow@hku.hk.
Jazyk: angličtina
Zdroj: Drug delivery and translational research [Drug Deliv Transl Res] 2024 Nov 01. Date of Electronic Publication: 2024 Nov 01.
DOI: 10.1007/s13346-024-01721-8
Abstrakt: Ischemic stroke is one of the major diseases causing varying degrees of dysfunction and disability worldwide. The current management of ischemic stroke poses significant challenges due to short therapeutic windows and limited efficacy, highlighting the pressing need for novel neuroprotective treatment strategies. Previous studies have shown that fingolimod (FIN) is a promising neuroprotective drug. Here, we report the rational development of FIN nano-embedded nasal powders using full factorial design experiments, aiming to provide rapid neuroprotection after ischemic stroke. Flash nanoprecipitation was employed to produce FIN nanosuspensions with the aid of polyvinylpyrrolidone and cholesterol as stabilizers. The optimized nanosuspension (particle size = 134.0 ± 0.6 nm, PDI = 0.179 ± 0.021, physical stability = 72 ± 0 h, and encapsulation efficiency of FIN = 90.67 ± 0.08%) was subsequently spray-dried into a dry powder, which exhibited excellent redispersibility (RdI = 1.09 ± 0.04) and satisfactory drug deposition in the olfactory region using a customized 3D-printed nasal cast (45.4%) and an Alberta Idealized Nasal Inlet model (8.6%) at 15 L/min. The safety of the optimized FIN nano-embedded dry powder was confirmed in cytotoxicity studies with nasal (RPMI 2650 and Calu-3 cells) and brain related cells (SH-SY5Y and PC 12 cells), while the neuroprotective effects were demonstrated by observed behavioral improvements and reduced cerebral infarct size in a middle cerebral artery occlusion mouse stroke model. The neuroprotective effect was further evidenced by increased expression of anti-apoptotic protein BCL-2 and decreased expression of pro-apoptotic proteins CC3 and BAX in brain peri-infarct tissues. Our findings highlight the potential of nasal delivery of FIN nano-embedded dry powder as a rapid neuroprotective treatment strategy for acute ischemic stroke.
(© 2024. The Author(s).)
Databáze: MEDLINE
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