Enhanced brain targeting and improved Alzheimer's disease therapy via intranasal delivery of Ginsenoside F1-loaded...

Alzheimer's disease (AD) progressively impairs cognition and memory, is pathologically localized in the cortex and hippocampus. Ginsenoside F1 (GF1), a rare ginsenoside, exerts great potential for AD treatment. However, the clinical translation is limited by its poor solubility and extremely low oral bioavailability (<1 %), which restricts its central nervous system (CNS) delivery and pathological site distribution via conventional formulations. Thus, the objective of this study is to explore the feasibility of increasing GF1 concentration in the brain via intranasal delivery, utilizing the solubilizing and permeation-enhancing capacity of nanomicelle in combination with borneol coadministration as a 'guider' to further enrich GF1 at the brain pathological sites. GF1-loaded single (GF1-M) and mixed micelles (GF1-MM) were successfully prepared and characterized. All the micelles had particle size less than 100 nm, with enhanced nasal mucosal permeability, and significantly increased GF1 concentration in the brain. The mixed micelles (GF1-1-BOR-MM) in combination with borneol further enhanced brain targeting efficiency of GF1, with a brain targeting index (DTI) of 1032.84 % and a nose-to-brain direct transport percentage (DTP) of 90.13 %. Borneol also significantly promoted GF1 distribution in the cortex and hippocampus, the pathological sites of AD. Pharmacodynamics studies demonstrated that after intranasal delivery, GF1-1-BOR-MM group showed substantial cognitive function improvement in AD model mice. In conclusion, intranasal drug delivery combined with nanomicelles breaks the deadlock of effective poorly soluble drug delivery to the brain. By combining with borneol, it can further enhance drug distribution to the pathologic site of AD, which holds great potential as a platform for treating CNS-related diseases.