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

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

doi:10.1016/j.ultsonch.2022.105986

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

Ultrason Sonochem. 2022 Apr:85:105986. doi: 10.1016/j.ultsonch.2022.105986. Epub 2022 Mar 23.

Authors

Affiliations

¹ Department of Clinical Medicine, University of Bergen, Bergen, Norway; National Centre for Ultrasound in Gastroenterology, Haukeland University Hospital, Bergen, Norway; Department of Physics, Norwegian University of Science and Technology, Trondheim, Norway; Neoety AS, Kløfta, Norway. Electronic address: Spiros@neoety.com.
² Department of Clinical Science, University of Bergen, Bergen, Norway.
³ Department of Clinical Science, University of Bergen, Bergen, Norway; Department of Quality and Development, Hospital Pharmacies Enterprise in Western Norway, Bergen, Norway.
⁴ Department of Physics, Norwegian University of Science and Technology, Trondheim, Norway; Department of Biotechnology and Nanomedicine, SINTEF Industry, Trondheim, Norway; Cancer Clinic, St. Olav's Hospital, Trondheim, Norway.
⁵ Department of Clinical Medicine, University of Bergen, Bergen, Norway; National Centre for Ultrasound in Gastroenterology, Haukeland University Hospital, Bergen, Norway; KinN Therapeutics, Bergen, Norway.
⁶ Department of Clinical Medicine, University of Bergen, Bergen, Norway; National Centre for Ultrasound in Gastroenterology, Haukeland University Hospital, Bergen, Norway.
⁷ Department of Biotechnology and Nanomedicine, SINTEF Industry, Trondheim, Norway.
⁸ Department of Circulation and Medical Imaging, Norwegian University of Science and Technology, Trondheim, Norway; Department of Health Research, SINTEF Digital, Trondheim, Norway.
⁹ Department of Clinical Science, University of Bergen, Bergen, Norway; CCBIO, Department of Clinical Science, University of Bergen, Norway.
¹⁰ Department of Clinical Science, University of Bergen, Bergen, Norway; KinN Therapeutics, Bergen, Norway.
¹¹ Polymer Technology, Eindhoven University of Technology, Eindhoven, the Netherlands.

Abstract

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.

Keywords: Antibubble; Microbubbles; Sonoporation; Targeted drug delivery; Ultrasound.

MeSH terms

Contrast Media
Drug Delivery Systems / methods
Emulsions
Microbubbles*
Nanoparticles*
Ultrasonography

Substances

Contrast Media
Emulsions