Cell-Penetrating Peptide-Modified Block Copolymer Micelles Promote Direct Brain Delivery via Intranasal Administration
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In order to develop non-invasive and effective nose-to-brain delivery of drugs, we synthesized Tat analog-modified methoxy poly(ethylene glycol) (MPEG)/poly(ε-caprolactone) (PCL) amphiphilic block copolymers through the ester bond.
We evaluated the brain distribution of coumarin, acting as a model chemical, after intravenous or intranasal administration of MPEG-PCL. In addition, cellular uptake of coumarin by rat glioma cells transfected with coumarin-loaded MPEG-PCL or MPEG-PCL-Tat was determined. Finally, we determined the brain distribution and biodistribution after intranasal administration of coumarin-loaded MPEG-PCL-Tat.
The amount of coumarin in the brain after intranasal administration was significantly higher than that after intravenous administration. In addition, cellular uptake of coumarin using MPEG-PCL was the lowest, while cellular uptake of coumarin using Tat-modified MPEG-PCL (MPEG-PCL-Tat) was higher than that of MPEG-PCL. Therefore, the brain distribution of coumarin administered using MPEG-PCL-Tat was significantly greater than that using MPEG-PCL. Then, the coumarin distribution after MPEG-PCL-Tat administration in non-targeted tissues (lung, liver, heart, kidney and spleen) was lower than that after coumarin administration without nanomicelles.
We have demonstrated that utilization of nano-sized micelles modified with Tat can facilitate direct intranasal brain delivery.
KEY WORDSbiodistribution brain tumors cell penetrating peptide intranasal brain delivery micelles
We thank Mr. Shohei Suzuki and Mr. Fuminari Akiyama (School of Pharmacy, Tokyo University of Pharmacy and Life Sciences) for their excellent technical assistance. We are also grateful to Prof. Tsunehiko Fukuda, Ph.D. (Nagahama Institute of Bio-Science and Technology) for the peptide synthesis. This study was supported in part by a grant for private universities provided by the Promotion and Mutual Aid Corporation for Private Schools of Japan.
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