Ultrasound-induced mild hyperthermia as a novel approach to increase drug uptake in brain microvessel endothelial cells
Abstract
Purpose Drug delivery to the central nervous system (CNS) is limited by the blood-brain barrier (BBB). Thus, a noninvasive and reversible method to enhance BBB permeation of drugs is highly desirable. In the present work, we studied if ultrasound-induced mild hyperthermia (USHT, 0.4 watts (W)/cm2 at 41 degrees C) can enhance drug absorption in BBB endothelial cells, and we elucidated the mechanism of USHT on cellular accumulation.Methods To accomplish these aims, we studied the effects of hyperthermia (41 degrees C), USHT, P-glycoprotein (P-gp) modulator (PSC 833), and combination of USHT and PSC 833 on accumulation of P-gp substrate (R123) and non-P-gp substrates (sucrose, 2-deoxyglucose, and antipyrine) in monolayers of primary bovine brain microvessel endothelial cells (BBMEC).Results USHT, through its thermal effect, produces a significant (relative to controls; no USHT) and comparable increase in R123 accumulation with PSC 833. We also demonstrate that USHT increases permeability of hydrophobic (R123 and [14C]-antipyrine) and not hydrophilic molecules ([14C]-sucrose and 2-[3H]-deoxy-D-glucose). The enhanced permeability is reversible and size dependent, as USHT produces a much larger effect on cellular accumulation of [14C]-antitpyrine (molecular weight of 188 D) than that of R123 (molecular weight of 380.8 D). Although USHT increases membrane permeability, it did not affect P-gp activity or the activity of glucose transporters.Conclusions Our results point to the potential use of USHT as a reversible and noninvasive approach to increase BBB permeation of hydrophobic drugs, including P-gp-recognized substrates.
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Ultrasound has been implicated as potential approach to promote cell entry owing to ultrasound-induced mild hyperthermia and cell membrane deformation.
“Additionally, ultrasound has also been implicated as a potential approach to promote cell entry owing to ultrasound-induced mild hyperthermia and cell membrane deformation [176, 177].”
From Non-viral delivery systems for CRISPR/Cas9-based genome editing: challenges and opportunities (2018) · cites this paper as [176]
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- Authors
- Cho, C.-W., Liu, Y., Cobb, W. N., Henthorn, T. K., Lillehei, K., Christians, U., & Ng, K.-Y.
- Corresponding author
- Ng, Ka-Yun
- Venue
- Pharmaceutical Research
- Published
- 2002-08
- Volume
- 19
- Issue
- 8
- Pages
- 1123-1129
- ISSN
- 0724-8741 (ISSN-L)
- 1573-904X
- OpenAlex
- W2182182551
- Cited by
- 69
- References
- 22
- Citations by year
- 2024: 2 · 2021: 1 · 2020: 1 · 2018: 5 · 2017: 1 · 2016: 2 · 2015: 4 · 2014: 5 · 2013: 6 · 2012: 6
- FWCI
- 3.27
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- Pharmaceutical Research (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Cancer Institute (CA79708)
- Topics
- Physical Sciences › Engineering › Biomedical Engineering › Ultrasound and Hyperthermia Applications
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Keywords
- blood-brain barrier permeability, brain microvascular endothelial cells, P-glycoprotein, PSC833, brain drug delivery, antipyrine, R123, glucose transporters, molecular weight dependence
- MeSH terms
- Animals, Brain, Cattle, Cells, Cultured, Endothelium, Vascular, Hyperthermia, Induced, Microcirculation, Ultrasonics, Drug Delivery Systems, Rats
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