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

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

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

3 Citations (Scopus)
11 Downloads (Pure)


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.

Original languageEnglish
Article number494
Issue number3
Early online date24 Feb 2022
Publication statusPublished - Mar 2022


  • Epithelial permeation
  • Intracellular accumulation
  • Microbubbles
  • Nanobody
  • Paracellular permeability
  • Ultrasound


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