The Effect of Microbubble-Assisted Ultrasound on Molecular Permeability across Cell Barriers.

Charis Rousou,Arto Urtti,Chrit Moonen,Sabrina Oliveira,Kim Van Der Wurff-Jacobs,Enrico Mastrobattista,Roel Deckers,Gert Storm,Josanne De Maar,Boning Qiu,Marika Ruponen

doi:10.3390/pharmaceutics14030494

Abstract

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.

Highlights

Introduction distributed under the terms andThe functionality and vitality of tissues depend on a proper regulation of their barriers [1,2,3]
In the absence of ultrasound and microbubbles (USMB) permeability was highest for propranolol and decreased with increasing molecular weight and decreasing LogD (Figure 2A)
Treatment of cells with USMB at increasing ultrasound pressures did not have a significant effect on the permeability of small molecules, despite their differences in hydrophilicity (Figure 2B–D)

Summary

Introduction

The functionality and vitality of tissues depend on a proper regulation of their barriers [1,2,3]. Tissue barriers are formed by layers of epithelial cells that separate organs from their environment, and endothelial cells in the vasculature (separating the bloodstream from the tissues). Examples of tissue barriers include the blood-retina barrier (BRB) in the conditions of the Creative Commons. Pharmaceutics 2022, 14, 494 posterior eye and the blood-brain barrier (BBB). The functions of these cellular barriers are critical for tissue, organ, and organism homeostasis. A factor of prime importance regulating their permeability is the presence of intercellular junctions between the cells [4]

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