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Developing Ultrasound-Activated Gemcitabine Delivery Systems for Chemoradiation Therapy in Muscle-Invasive Bladder Cancer

Jia-Ling Ruan1*, Richard Browning1, Yesna Yildiz1, Luca Bau2, James Thompson1, Amy Elliott1, Sean Smart1, Lisa Folkes1, Alix Hampson1, Estelle Beguin2, Michael Gray2, Borivoj Vojnovic1, Eleanor Stride2 and Anne E. Kiltie1
  • 1 Department of Oncology, Medical Sciences Division, University of Oxford, United Kingdom
  • 2 Institute of Biomedical Engineering, Department of Engineering Science, University of Oxford, United Kingdom

Background: Bladder cancer is the fifth most common cancer in the UK with a high incidence rate in the elderly population. Since this population is not suitable for surgery, chemoradiation therapy has become a widely-used bladder preservation method in managing muscle-invasive bladder cancers. Chemotherapeutic drugs like gemcitabine are able to enhance the radiosensitisation of tumours, but most of them still carry systematic side effects to normal tissues. Method: In this project, we primarily aim to improve the chemoradiation treatment efficacy by developing two novel gemcitabine delivery systems that can be coupled with ultrasound for controlled drug release. In the first system, gemcitabine was incorporated into liposomal nanoparticles and these liposomes were then bio-conjugated to microbubbles. In the second system, gemcitabine was co-delivered with microbubbles. The particle size, concentration, and morphology of both systems were characterized by dynamic light scattering, nanoparticle tracking analysis, and microscopy. The stability of gemcitabine in both systems was also assessed. The ultrasound-mediated delivery efficacy was investigated using both in vitro bladder cancer cell models and in vivo orthotopic muscle-invasive bladder cancer models. Results: Encapsulation of gemcitabine into liposomes demonstrated prolonged gemcitabine retention both in vitro and in vivo compared to free gemcitabine. However, ultrasound-mediated gemcitabine delivery by liposomal conjugated microbubbles did not further increase the gemcitabine uptake in the bladder tumour compared to direct liposome administration. An investigation into the tumour microenvironment demonstrated the effect of gemcitabine uptake was correlated with the vascularity of the tumour. Conclusion: Our findings indicate that ultrasound-mediated gemcitabine delivery could be a promising new approach for improving chemoradiation therapy in muscle-invasive bladder cancer. However, stratifying the tumour type based on the tumour microenvironment would be necessary for efficient delivery using microbubbles due to their size limitation. We are now investigating if nanobubbles can be better delivery vehicles for ultrasound-mediated drug delivery.

Keywords: ultrasound-mediated drug delivery, chemoradiation (CRT), Muscle-invasive bladder cancer (MIBC), Liposome, orthotopic animal model, gemcitabine (GEM)

Conference: Bladder Cancer Translational Research Meeting, London, United Kingdom, 29 Mar - 29 Mar, 2019.

Presentation Type: Oral

Topic: Development of personalised treatment

Citation: Ruan J, Browning R, Yildiz Y, Bau L, Thompson J, Elliott A, Smart S, Folkes L, Hampson A, Beguin E, Gray M, Vojnovic B, Stride E and Kiltie AE (2019). Developing Ultrasound-Activated Gemcitabine Delivery Systems for Chemoradiation Therapy in Muscle-Invasive Bladder Cancer. Front. Oncol. Conference Abstract: Bladder Cancer Translational Research Meeting. doi: 10.3389/conf.fonc.2019.01.00006

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Received: 27 Feb 2019; Published Online: 27 Sep 2019.

* Correspondence: Dr. Jia-Ling Ruan, Department of Oncology, Medical Sciences Division, University of Oxford, Oxford, England, OX3 7DQ, United Kingdom, jia-ling.ruan@oncology.ox.ac.uk