SonoVue® vs. Sonazoid™ vs. Optison™: Which Bubble Is Best for Low-Intensity Sonoporation of Pancreatic Ductal Adenocarcinoma?

Spiros Kotopoulis,Emmet Mc Cormack,Mihaela Popa,Elisa Murvold,Ragnhild Haugse,Anika Langer,Mireia Mayoral Safont,Odd Helge Gilja,Christina Lam,Georg Dimcevski,Tormod Bjånes

doi:10.3390/pharmaceutics14010098

Spiros Kotopoulis, Emmet Mc Cormack + Show 9 more

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https://doi.org/10.3390/pharmaceutics14010098

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Abstract

The use of ultrasound and microbubbles to enhance therapeutic efficacy (sonoporation) has shown great promise in cancer therapy from in vitro to ongoing clinical studies. The fastest bench-to-bedside translation involves the use of ultrasound contrast agents (microbubbles) and clinical diagnostic scanners. Despite substantial research in this field, it is currently not known which of these microbubbles result in the greatest enhancement of therapy within the applied conditions. Three microbubble formulations—SonoVue®, Sonazoid™, and Optison™—were physiochemically and acoustically characterized. The microbubble response to the ultrasound pulses used in vivo was simulated via a Rayleigh–Plesset type equation. The three formulations were compared in vitro for permeabilization efficacy in three different pancreatic cancer cell lines, and in vivo, using an orthotopic pancreatic cancer (PDAC) murine model. The mice were treated using one of the three formulations exposed to ultrasound from a GE Logiq E9 and C1-5 ultrasound transducer. Characterisation of the microbubbles showed a rapid degradation in concentration, shape, and/or size for both SonoVue® and Optison™ within 30 min of reconstitution/opening. Sonazoid™ showed no degradation after 1 h. Attenuation measurements indicated that SonoVue® was the softest bubble followed by Sonazoid™ then Optison™. Sonazoid™ emitted nonlinear ultrasound at the lowest MIs followed by Optison™, then SonoVue®. Simulations indicated that SonoVue® would be the most effective bubble using the evaluated ultrasound conditions. This was verified in the pre-clinical PDAC model demonstrated by improved survival and largest tumor growth inhibition. In vitro results indicated that the best microbubble formulation depends on the ultrasound parameters and concentration used, with SonoVue® being best at lower intensities and Sonazoid™ at higher intensities.

Highlights

Sonoporation was initially defined as the transient formation and resealing of pores in a cell membrane due to combined microbubble and ultrasound (US) treatment, which may be used therapeutically to increase uptake and entrapment of drugs or genes in cells [1,2].Sonoporation is promising for enhancing the treatment of cancer, a leading cause of morbidity and mortality worldwide
To provide a better understanding, we have investigated the impact of sonoporation on the in vitro uptake of molecules, over a range of microbubble concentrations and ultrasound intensities, and on the in vivo efficacy of sonoporation and paclitaxel (PTX)
The in vitro experiments performed in this study indicate that both the type of microbubble and microbubble concentration, the ultrasound intensity, as well as the cell type all affect sonoporation efficacy

Summary

Introduction

Sonoporation was initially defined as the transient formation and resealing of pores in a cell membrane due to combined microbubble and ultrasound (US) treatment, which may be used therapeutically to increase uptake and entrapment of drugs or genes in cells [1,2].Sonoporation is promising for enhancing the treatment of cancer, a leading cause of morbidity and mortality worldwide. Most of the research done to solve the drug delivery problem focuses on the development of drug carriers like liposomes and nanoparticles, taking advantage of passive enhanced permeability and retention effect (EPR-effect) [6,7,8]. Though the main advantage is reduction of side effects instead of the improvement of overall survival compared to free drug [6,7], this kind of targeted drug delivery has still not fully met the expectations, as the enhancement of drug delivery by passively relying on the EPR effect is too limited and heterogenous [7,8]. It has been suggested to use vessel-modulating strategies, including physical methods such as sonoporation, to improve efficiency and specificity of the EPR effect [7]

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