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MedViz Lighthouse Project – Multimodal imaging and ultrasound microbubble drug delivery in targeted cancer therapy
A major limitation in conventional chemotherapy is the inability to deliver enough of the therapeutic agent to the target region.
Sonoporation, the use of ultrasound and microbubbles to enhance therapeutic efficacy in a targeted location, may be a solution
to this limitation. This MedViz Lighthouse project has been focused on understanding, elucidating, and applying sonoporation
from lab-to-bench side.
The project focused on pancreatic cancer, a disease characterized by a dense tumor structure located deep in an internal organ,
limiting surgical intervention and likely restricting uptake of chemotherapy in the fibrous tumor. Two years survival is 35%
and 5 years survival is 12%, and new therapeutic development is desperately needed.
Microbubbles
In this project we have initially used commercial microbubbles (SonoVue®) to induce sonoporation. These microbubbles are
originally designed for imaging and not therapy. The wide size distribution results in a continuously changing variable that we
have no control over. Hence, we have initiated developing our own microbubbles using a microfluidic platform. We are able to
manufacture microbubbles with a very narrow size distribution (±0.1µm vs ±3µm) using the same compounds as the clinical
counterparts. We have also initiated developing and fully simulated a drug cored microbubble known as the antibubble
potentially allowing for target drug delivery and therapy.
In vitro experiments
A bespoke experimental configuration was developed to induce sonoporation with controlled, pre-defined ultrasound
conditions in vitro. This modular setup was designed to treat either adherent or floating cells. Initial results show that the
ultrasound pulse length and amplitude, and microbubble concentration all influence the efficiency of enhanced uptake.
Experiments using clinical probes showed that ultrasound and microbubbles affect intracellular signaling pathways such as
ERK, p53 and p38. This suggest novel biomarkers to be employed for effective development of sonoporation on tumours.
Pre-clinical experiments
Pre-clinical murine experiments showed that sonoporation using SonoVue® significantly inhibit tumour growth in an
orthotopic model of pancreatic cancer. Inducing sonoporation with a novel phase change microbubble formulation, we saw
tumour volume recession, and sustained tumour vascular.
Clinical Trials
A Phase I clinical trial focused on treating patients with inoperable pancreatic ductal adenocarcinoma using SonoVue® and a
clinical diagnostic ultrasound system resulted in a near doubling of survival compared to historical controls, and a prolonged
period of health with no additional side effects.
References:
Dimcevski G, Kotopoulis S, Bjånes T, Hoem D, Schjøtt J, Gjertsen BT, Biermann M, Molven A, Sorbye H, McCormack E,
Postema M, Gilja OH. A human clinical trial using ultrasound and microbubbles to enhance gemcitabine treatment of
inoperable pancreatic cancer. J Control Release. 2016;243:
Kotopoulis S, Delalande A, Popa M, Mamaeva V, Dimcevski G, Gilja OH, Postema M, Gjertsen BT, McCormack E.
Sonoporation-enhanced chemotherapy significantly reduces primary tumour burden in an orthotopic pancreatic cancer
xenograft. Mol Imaging Biol. 2014;16(1):53-62.
Prof. Bjørn Tore Gjertsen
Prof. Emmet Mc Cormack
Researcher Spiros Kotopoulis
Associate Prof. Georg Dimcevski