title: Ultrasound-induced mild hyperthermia as a novel approach to increase drug uptake in brain microvessel endothelial cells.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado Health Sciences Center, Denver 80262, USA.
authors.forename: Cheong-Weon
authors.initials: CW
authors.lastname: Cho
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
authors.forename: Wesley N
authors.initials: WN
authors.lastname: Cobb
authors.forename: Thomas K
authors.initials: TK
authors.lastname: Henthorn
authors.forename: Kevin
authors.initials: K
authors.lastname: Lillehei
authors.forename: Uwe
authors.initials: U
authors.lastname: Christians
authors.forename: Ka-Yun
authors.initials: KY
authors.lastname: Ng
mesh_terms: D000818:Animals; D001921:Brain / Q000098:blood supply / Q000166:cytology / Q000378:metabolism*; D002417:Cattle; D002478:Cells, Cultured; D016503:Drug Delivery Systems / Q000379:methods*; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism*; D006979:Hyperthermia, Induced / Q000379:methods; D008833:Microcirculation / Q000166:cytology / Q000378:metabolism; D051381:Rats; D014465:Ultrasonics