Evaluation of the targeted delivery of 5-fluorouracil and ascorbic acid into the brain with ultrasound-responsive nanobubbles

Abstract

Recently, ultrasound-induced drug delivery into the brain using bubble formulations has been developed. After the brain delivery, however, the information on pharmacokinetics of hydrophilic drugs in the brain is lacking. In this study, to clarify the time-course pharmacokinetics of hydrophilic drugs, we used a brain microdialysis method. Using ultrasound-responsive nanobubbles (bubble liposomes (BLs)) with ultrasound irradiation, two hydrophilic drugs, 5-fluorouracil (5-FU) and ascorbic acid, were delivered into the brain of mice and rats and their time-course pharmacokinetics were evaluated with microdialysis. The results indicated that the time-course pharmacodynamics of ascorbic acid evaluated by examining its antioxidant capacity supported the time-course pharmacokinetics. Additionally, to strengthen the evidences of our evaluation, we varied the effect of BLs dose and duration and intensity of ultrasound irradiation on drug delivery. Among them, when the dose of BLs was changed, the trend of 5-FU intracerebral migration was consistent with other report. In conclusion, we succeeded in clarifying the time-course pharmacokinetics of the two hydrophilic drugs after the brain delivery with bubble formulations and ultrasound irradiation using mice and rats.

Keywords:

• Drug delivery system
• ultrasound
• bubble liposomes
• blood-brain barrier
• brain microdialysis

Disclosure statement

The authors report no conflicts of interest.

Additional information

Funding

This work was supported by JSPS KAKENHI Grant Number 16K18862, the Sasakawa Scientific Research Grant from the Japan Science Society, the Shin-Nihon Foundation of Advanced Medical Research and Takeda Science Foundation.