Formulation and characterisation of drug-loaded antibubbles for image-guided and ultrasound-triggered drug delivery

• DOI: 10.1016/j.ultsonch.2022.105986
• Publication Date: 2022-03-23T07:08:16Z
• Authors: Spiros Kotopoulis; Christina Lam; Ragnhild Haugse; Sofie Snipstad; Elisa Murvold; Tæraneh Jouleh; Sigrid Berg; Rune Hansen; Mihaela Popa; Emmet Mc Cormack; Odd Helge Gilja; Albert Poortinga
• Keywords: Targeted drug delivery; 0303 health sciences; Microbubbles; Short Communication; Acoustics. Sound; QC221-246; 610; Contrast Media; Antibubble; 3. Good health; Chemistry; 03 medical and health sciences; Drug Delivery Systems; Sonoporation; Ultrasound; Nanoparticles; Emulsions; QD1-999; Ultrasonography

The aim of this study was to develop high load-capacity antibubbles that can be visualized using diagnostic ultrasound and the encapsulated drug can be released and delivered using clinically translatable ultrasound. The antibubbles were developed by optimising a silica nanoparticle stabilised double emulsion template. We produced an emulsion with a mean size diameter of 4.23 ± 1.63 µm where 38.9 ± 3.1% of the droplets contained a one or more cores. Following conversion to antibubbles, the mean size decreased to 2.96 ± 1.94 µm where 99% of antibubbles were <10 µm. The antibubbles had a peak attenuation of 4.8 dB/cm at 3.0 MHz at a concentration of 200 × 103 particles/mL and showed distinct attenuation spikes at frequencies between 5.5 and 13.5 MHz. No increase in subharmonic response was observed for the antibubbles in contrast to SonoVue®. High-speed imaging revealed that antibubbles can release their cores at MIs of 0.6. In vivo imaging indicated that the antibubbles have a long half-life of 68.49 s vs. 40.02 s for SonoVue®. The antibubbles could be visualised using diagnostic ultrasound and could be disrupted at MIs of ≥0.6. The in vitro drug delivery results showed that antibubbles can significantly improve drug delivery (p < 0.0001) and deliver the drug within the antibubbles. In conclusion antibubbles are a viable concept for ultrasound guided drug delivery.