In this study we compared three different microbubble-based approaches to the delivery of a widely used chemotherapy drug, gemcitabine: (i) co-administration of gemcitabine and microbubbles (Gem+MB); (ii) conjugates of microbubbles and gemcitabine-loaded liposomes (GemlipoMB); and (iii) microbubbles with gemcitabine directly bound to their surfaces (GembioMB). Both in vitro and in vivo investigations were carried out, respectively, in the RT112 bladder cancer cell line and in a murine orthotopic muscle-invasive bladder cancer model. The in vitro (in vivo) ultrasound exposure conditions were a 1 (1.1) MHz centre frequency, 0.07 (1.0) MPa peak negative pressure, 3000 (20,000) cycles and 100 (0.5) Hz pulse repetition frequency. Ultrasound exposure produced no significant increase in drug uptake either in vitro or in vivo compared with the drug-only control for co-administered gemcitabine and microbubbles. In vivo, GemlipoMB prolonged the plasma circulation time of gemcitabine, but only GembioMB produced a statistically significant increase in cleaved caspase 3 expression in the tumor, indicative of gemcitabine-induced apoptosis.
|Number of pages||20|
|Journal||Ultrasound in Medicine and Biology|
|Early online date||8 Mar 2021|
|Publication status||Published - 1 Jun 2021|
Bibliographical noteFunding Information:
The financial support from Cancer Research UK and the Engineering and Physical Sciences Research Council (EPSRC) (Multidisciplinary Project Grant C5255/A15935) is gratefully acknowledged. We thank Dr. Errin Johnson of the Dunn School of Pathology for assistance with the electron microscopy. We thank the staff of the IBME mechanical workshop (Mr. James Fisk and Mr. David Salisbury) for assistance with development of the ultrasound apparatus. We thank Ms. Karla Watson and Magdalena Hutchins of the Oncology Biomedical Science Unit for assistance with animal maintenance. John Callan, Anthony McHale and Eleanor Stride are co-founders of a spin out company, SonoTarg Ltd. and inventors on a patent (US20180344872A1) which covers one of the formulations reported in this paper. There was, however, no involvement of SonoTarg in the design, conduct or funding of this study and SonoTarg is not currently pursuing applications in chemoradiation therapy.
- Bladder cancer
- Orthotopic model
- Ultrasound-mediated drug delivery