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.
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.
Authors: C Cordon-Cardo; J P O'Brien; D Casals; L Rittman-Grauer; J L Biedler; M R Melamed; J R Bertino Journal: Proc Natl Acad Sci U S A Date: 1989-01 Impact factor: 11.205
Authors: Robert M Koffie; Christian T Farrar; Laiq-Jan Saidi; Christopher M William; Bradley T Hyman; Tara L Spires-Jones Journal: Proc Natl Acad Sci U S A Date: 2011-11-07 Impact factor: 11.205
Authors: Carl D Herickhoff; Christy M Wilson; Gerald A Grant; Gavin W Britz; Edward D Light; Mark L Palmeri; Patrick D Wolf; Stephen W Smith Journal: Ultrasound Med Biol Date: 2011-08-19 Impact factor: 2.998
Authors: Carl D Herickhoff; Edward D Light; Kristin F Bing; Srinivasan Mukundan; Gerald A Grant; Patrick D Wolf; Stephen W Smith Journal: Ultrason Imaging Date: 2009-04 Impact factor: 1.578