Intranasal delivery of metformin using metal-organic framework (MOF)-74-Mg nanocarriers.

Dosage tolerance is one of the translational challenges of using metformin (Met) in brain therapeutics. This paper presents metal-organic framework (MOF)-74-Mg nanocarriers (NCs) for intranasal (IN) delivery of brain-specific agents with a prolonged release time. We confirmed their excellent biocompatibility (5 mg/mL) and intrinsic fluorescence properties (370/500 nm excitation/emission peak) in Neuro-2A cells. This NC exhibited a high Met loading rate (10% wt/wt) and a sustained and prolonged release pattern of Met (90% release in 16 h) in Dulbecco's Modified Eagle Medium. We observed an optimal brain accumulation of Met-MOF (9% of the injected dosage) 8 h after IN injection. This percentage is at least 82 times higher than oral administration. Confocal imaging demonstrated significantly higher uptake of Met-MOF, 45 min after IN injection, by 79-85% neurons and 93-97% microglia than astrocytes and oligodendrocytes across 5xFAD mouse brain regions, including hippocampus and striatum. These results suggest MOF-74-Mg is a potential NC for high brain Met accumulation, real-time imaging, and prolonged and sustained release of Met and other neurotherapeutic agents that are challenging to deliver using traditional carriers and administration routes.