Ultrasound-induced mild hyperthermia as a novel approach to increase drug uptake in brain microvessel endothelial cells. Journal Article uri icon



  • 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.

publication date

  • August 1, 2002

Date in CU Experts

  • November 12, 2017 2:35 AM

Full Author List

  • Cho C-W; Liu Y; Cobb WN; Henthorn TK; Lillehei K; Christians U; Ng K-Y

author count

  • 7

Other Profiles

International Standard Serial Number (ISSN)

  • 0724-8741

Additional Document Info

start page

  • 1123

end page

  • 1129


  • 19


  • 8