Ultrasound-Stimulated Phase-Change Contrast Agents for Transepithelial Delivery of Macromolecules, Toward Gastrointestinal Drug Delivery

Abstract

The gastrointestinal (GI) tract presents a notoriously difficult barrier for macromolecular drug delivery, especially for biologics. Herein, we demonstrate that ultrasound-stimulated phase change contrast agents (PCCAs) can transiently disrupt Caco-2 monolayers and improve the transepithelial transport of a macromolecular model drug. With ultrasound treatment in the presence of PCCAs, we achieved a maximum of 44±15% transepithelial delivery of 70 kDa FITCdextran, compared to negligible delivery through sham control monolayers. Among all tested rarefactional pressures (300-600 kPa), dextran delivery efficiency was consistently greatest at 300 kPa. To explore this unexpected finding, we quantified stable and inertial cavitation energy generated by various ultrasound exposure conditions. In general, lower pressures resulted in more persistent cavitation activity over 30 second exposure times, which may explain the enhanced dextran delivery efficiency. Thus, a unique advantage of using low boiling point PCCAs for this application is that the same low-pressure pulses can be used to induce vaporization and provide maximal delivery.

Harnessing Ultrasound-Stimulated Phase Change Contrast Agents to Improve Antibiotic Efficacy Against Methicillin-Resistant Staphylococcus aureus Biofilms

“…The lower pressures, 300 and 600kPa, in combination with PCCA were determined to be most effective at potentiating tobramycin efficacy. This is consistent with our previous findings where lower pressures (above the ADV threshold) resulted in more persistent cavitation activity during a 30s ultrasound exposure and was consistently greatest at macromolecule drug delivery across colorectal adenocarcinoma monolayers 25 .…”

“…1 to 10% in Fig. 2—3 as this was shown to have a more modest effect in our prior work and resulted in significant drug delivery 25 . Where indicated, 10μl of PCCA was added to each well ((1.17 ± 0.4) ×10 11 particles / mL, 0.18 μm diameter) and mixed gently by pipetting.…”

“…1a). In contrast, levofloxacin and gentamicin showed no efficacy against biofilms at clinically achievable concentrations found in serum (Cmax) 24,25 (Fig. 1a).…”

“…Ultrasound experiments were conducted in 12 or 24 well tissue culture plates using a custom fabricated water bath ultrasound alignment setup to maintain 37C during the experiment, similar to a design used previously with cell monolayers 25 . Briefly, alignment guides were positioned above the wells to ensure reproducible transducer placement to the center of each well on top of the biofilm and 10mm from their bottom.…”

Transcranial activation and imaging of low boiling point phase‐change contrast agents through the temporal bone using an ultrafast interframe activation ultrasound sequence

“…Besides increased penetration, low frequency transmit would potentially favor the vaporization and cavitation of low boiling point PCCAs and thus enhance therapeutic effects. 56,57 To the best of our knowledge, there are no previous reports of imaging low boiling point PCCAs in this frequency range. Thus initial low frequency PCCA imaging studies were performed in a tissue-mimicking phantom without the skull before proceeding to evaluation of transcranial activation and imaging through the temporal bone.…”