SonoPlus+: Smart-bubble cancer therapy using ultrasound

This year (2015) two pre-clinical studies (in collaboration with industry) and three independent sub-projects in collaboration with international partners were completed. Preclinical Study 1 was the evaluation of a new type of microbubble fabricated by Phoenix Solution AS. This bubble is an emulation of the commercial ultrasound contrast agent Sonazoid and PFX & drug loaded oil droplets. Upon ultrasound activation, these PFX droplets vaporise releasing the drug in a targeted location and the microbubbles expand to 10x their original size, transiently inhibiting blood flow, increasing local drug concentration, and inducing ultrasound & microbubble mediated therapy. This combined treatment is know as Acoustic Cluster Therpay (ACT). These bubbles were tested on a sub-cutaneous pancreatic adenocarcinoma tumour over a 50 days. Paclitaxel was the chemotherapeutic agent used. Five groups were evaluated: Control 1 (No treatment), Control 2 (Paclitaxel (IP)), Treatment 1 (ACT bubbles (IV)+ Paclitaxel (IP)), Treatment 2 (ACT bubbles with paclitaxel embedded (IV) + Paclitaxel (IP)), and Treatment 3 (ACT bubbles alone (IV)). Results showed that after a single treatment the tumour volume was reduced but subsequently partially recovered. This trend was continuously observed till end of treatment. The tumour volume was statistically significant when compared to the drug alone after two treatments (p=0.037). No effect was seen when treating with the microbubbles alone. Tumour vascularization was also affected by the treatment where a sustained increase in active vasculature, as measured by 3D Power Doppler, was observed in the group treated ACT with Paclitaxel embedded. In conclusion, this pre-clinical study indicated that these first-in-kind microbubbles have the ability to transiently reduce tumour volume and this combined therapy has an effect on the tumour vasculature. Preclinical Study 2 was a study performed to compare if different commercial microbubbles have different efficacy in inducing ultrasound mediated drug delivery. The study was performed in collaboration with GE global research and GE healthcare. The results of this study show great promise but are currently under a non-disclosure agreement (NDA) and cannot be published. Subproject 1 was dedicated on developing novel microbubble formulations optimised for ultrasound guided drug delivery and physio-chemical characterisation of commercial and experimental microbubbles. Using Nitrogen controlled fluidic pumps and X-junction microfluidic junction we were able to generate microbubbles with d90/d10 values of approximate 1.02. In comparison the commercial microbubbles showed d90/d10 values of 2.0. The perfect mono dispersed bubbles would have a d90/d10 values of 1, the higher the value the more polydisperse the particles. Multi-parametric maps were performed allowing us to tailor the microbubble size, shell thickness, concentration, and polydispersity on demand. Physiochemical characterisation also allowed us to directly measured the electrophoretic mobility of microbubbles with diameters of <4 micrometers. This essential information allows us reduce toxicity and improve the dispersion and stability. This research project is part of an on-going international masters project in collaboration with the National Technical University of Athens, Greece. Subproject 2 focused on the completion and publication of an in vitro experimental platform that allows high-throughput evaluation of sonoporation conditions such as ultrasound pressure, power, and duty cycle, microbubble concentration and type. These devices have now been put into experimental used were cell extraction and characterisation protocols are being developed. Subproject 3 focused on the mathematical simulation and prediction of a novel microbubble format known as the antibubble. Subprojects 1 and 2 resulted in the completion of a Masters Thesis at the Department of Physics and Technology at The University of Bergen. The completion of research performed this year provides a critical stepping stone on fully understanding this therapeutic modality in order to optimise it and lead onto Phase II clinical trials. The results from the pre-clinical animal models indicate that the type of ultrasound conditions and microbubbles used need to be strongly considered as they have a significant impact on the therapeutic efficacy. The physio-chemical characterisation showed that the microbubble concentration can vary significantly from vial to vial and reduces as a function of time. Being able to predict these changes and implement them into both therapy and diagnostic regime may significantly improve their efficacy. In conclusion, the work performed on this project has a long term impact on health services as this therapeutic technique, once fully developed and optimised will significantly improve the therapeutic efficacy of a vast range of drugs along a multiple forms of cancers, improving quality of life, survival and reducing the financial strain on health services.