Ultrasound-induced mild hyperthermia as a novel approach to increase drug uptake in brain microvessel endothelial cells
Ultrasound-induced mild hyperthermia as a novel approach to increase drug uptake in brain microvessel endothelial cells
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DOI：
10.1023/a:1019837923906
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发表时间：
2002-08-01
影响因子：
3.7
通讯作者：
Ng, KY
中科院分区：
文献类型：
--
作者：
Cho, CW;Liu, Y;Ng, KY
目的.药物递送至中枢神经系统（CNS）受到血脑屏障（BBB）的限制。因此，非常需要一种增强药物的BBB渗透的非侵入性和可逆的方法。在本工作中，我们研究了超声诱导的轻度热疗（USHT，0.4W/cm（2），41 ℃）是否能增强血脑屏障内皮细胞对药物的吸收，并阐明了USHT对细胞蓄积的作用机制。为了实现这些目标，我们研究了高温（41 ℃）、USHT、P-糖蛋白（P-gp）调节剂（PSC 833）以及USHT和PSC 833的组合对原代牛脑微血管内皮细胞（BBMEC）单层中P-gp底物（R123）和非P-gp底物（蔗糖、2-脱氧葡萄糖和安替比林）积累的影响。USHT通过其热效应，使PSC 833的R123蓄积显著增加（相对于对照;无USHT）且相当。我们还证明，USHT增加了疏水性分子（R123和[C-14]-安替比林）而不是亲水性分子（[C-14]-蔗糖和2-[H-3]-脱氧-d-葡萄糖）的渗透性。由于USHT对[C-14]-安替比林（分子量为188 D）的细胞蓄积产生的影响远大于R123（分子量为380.8 D），因此渗透性的增强是可逆的，且依赖于尺寸。USHT虽然增加了细胞膜通透性，但不影响P-gp活性和葡萄糖转运蛋白的活性。我们的研究结果指出，USHT作为一种可逆的和非侵入性的方法，以增加血脑屏障渗透的疏水药物，包括P-gp识别的底物的潜在用途。
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)/cm(2) at 41degreesC) 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 (41degreesC), 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 [C-14]-antipyrine) and not hydrophilic molecules ([C-14]-sucrose and 2-[H-3]-deoxy-d-glucose). The enhanced permeability is reversible and size dependent, as USHT produces a much larger effect on cellular accumulation of [C-14]-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.