Rousou Charis, de Maar Josanne, Qiu Boning, van der Wurff-Jacobs Kim, Ruponen Marika, Urtti Arto, Oliveira Sabrina, Moonen Chrit, Storm Gert, Mastrobattista Enrico, Deckers Roel
Department of Pharmaceutical Sciences, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Heidelberglaan 8, 3584 CS Utrecht, The Netherlands.
Imaging and Oncology Division, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands.
Pharmaceutics. 2022 Feb 24;14(3):494. doi: 10.3390/pharmaceutics14030494.
The combination of ultrasound and microbubbles (USMB) has been applied to enhance drug permeability across tissue barriers. Most studies focused on only one physicochemical aspect (i.e., molecular weight of the delivered molecule). Using an in vitro epithelial (MDCK II) cell barrier, we examined the effects of USMB on the permeability of five molecules varying in molecular weight (182 Da to 20 kDa) and hydrophilicity (LogD at pH 7.4 from 1.5 to highly hydrophilic). Treatment of cells with USMB at increasing ultrasound pressures did not have a significant effect on the permeability of small molecules (molecular weight 259 to 376 Da), despite their differences in hydrophilicity (LogD at pH 7.4 from -3.2 to 1.5). The largest molecules (molecular weight 4 and 20 kDa) showed the highest increase in the epithelial permeability (3-7-fold). Simultaneously, USMB enhanced intracellular accumulation of the same molecules. In the case of the clinically relevant anti- C-X-C Chemokine Receptor Type 4 (CXCR4) nanobody (molecular weight 15 kDa), USMB enhanced paracellular permeability by two-fold and increased binding to retinoblastoma cells by five-fold. Consequently, USMB is a potential tool to improve the efficacy and safety of the delivery of drugs to organs protected by tissue barriers, such as the eye and the brain.
超声与微泡（USMB）联合应用已被用于增强药物透过组织屏障的通透性。大多数研究仅聚焦于一个物理化学方面（即所递送分子的分子量）。利用体外上皮（MDCK II）细胞屏障，我们研究了USMB对五种分子量（182道尔顿至20千道尔顿）和亲水性（pH 7.4时的LogD值从1.5至高度亲水）各异的分子通透性的影响。在不断增加的超声压力下用USMB处理细胞，对小分子（分子量259至376道尔顿）的通透性没有显著影响，尽管它们的亲水性存在差异（pH 7.4时的LogD值从-3.2至1.5）。最大的分子（分子量4和20千道尔顿）在上皮通透性方面表现出最高的增加（3至7倍）。同时，USMB增强了相同分子的细胞内蓄积。对于临床相关的抗C-X-C趋化因子受体4型（CXCR4）纳米抗体（分子量15千道尔顿），USMB使细胞旁通透性提高了两倍，并使与视网膜母细胞瘤细胞的结合增加了五倍。因此，USMB是一种潜在的工具，可用于提高向受组织屏障保护的器官（如眼睛和大脑）给药的疗效和安全性。
