Optimal timing for drug delivery into the hippocampus by focused ultrasound: A comparison of hydrophilic and lipophilic compounds

Younghee Seo; Kyung Won Chang; Jihyeon Lee; Chanho Kong; Jaewoo Shin; Jin Woo Chang; Young Cheol Na; Won Seok Chang

doi:10.1016/j.heliyon.2024.e29480

Optimal timing for drug delivery into the hippocampus by focused ultrasound: A comparison of hydrophilic and lipophilic compounds

Heliyon. 2024 Apr 9;10(8):e29480. doi: 10.1016/j.heliyon.2024.e29480. eCollection 2024 Apr 30.

Authors

Younghee Seo^{1

2}, Kyung Won Chang¹, Jihyeon Lee³, Chanho Kong¹, Jaewoo Shin⁴, Jin Woo Chang^{1

2}, Young Cheol Na^{1

5}, Won Seok Chang¹

Affiliations

¹ Department of Neurosurgery and Brain Research Institute, Yonsei University College of Medicine, Seoul, South Korea.
² Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, Seoul, South Korea.
³ Celros Biotech, Seoul, South Korea.
⁴ Medical Device Development Center, Daegu-Gyeongbuk Medical Innovation Foundation (K-MEDI Hub), Daegu, 41061, South Korea.
⁵ Department of Neurosurgery, Catholic Kwandong University College of Medicine, International St. Mary's Hospital, Incheon Metropolitan City, South Korea.

Abstract

Aims: Previous studies have reported that focused ultrasound (FUS) helps modulate the blood-brain barrier (BBB). These studies have generally used the paracellular pathway owing to tight junction proteins (TJPs) regulation. However, BBB transport pathways also include diffusion and transcytosis. Few studies have examined transcellular transport across endothelial cells. We supposed that increased BBB permeability caused by FUS may affect transcytosis. We investigated drug delivery through transcytosis and paracellular transport to the brain after BBB modulation using FUS.

Main methods: FUS and microbubbles were applied to the hippocampus of rats, and were euthanized at 1, 4, 24, and 48 h after sonication. To investigate paracellular transport, we analyzed TJPs, including zona occludens-1 (ZO-1) and occludin. We also investigated caveola-mediated transcytosis by analyzing caveola formation and major facilitator superfamily domain-containing 2a (Mfsd2a) levels, which inhibit caveola vesicle formation.

Key findings: One hour after FUS, ZO-1 and occludin expression was the lowest and gradually increased over time, returning to baseline 24 h after FUS treatment. Compared with that of TJPs, caveola formation started to increase 1 h after FUS treatment and peaked at 4 h after FUS treatment before returning to baseline by 48 h after FUS treatment. Decreased Mfsd2a levels were observed at 1 h and 4 h after FUS treatment, indicating increased caveola formation.

Significance: FUS induces BBB permeability changes and regulates both paracellular transport and caveola-mediated transcytosis. However, a time difference was observed between these two mechanisms. Hence, when delivering drugs into the brain after FUS, the optimal drug administration timing should be determined by the mechanism by which each drug passes through the BBB.

Keywords: Blood-brain barrier; Caveolae; Focused ultrasound; Major facilitator superfamily domain-containing 2a (Mfsd2a); Transcytosis; tight junction.