Evaluation of Loading Strategies to Improve Tumor Uptake of Gemcitabine in a Murine Orthotopic Bladder Cancer Model Using Ultrasound and Microbubbles

Jia Ling Ruan; Richard J. Browning; Yesna O. Yildiz; Luca Bau; Sukanta Kamila; Michael D. Gray; Lisa Folkes; Alix Hampson; Anthony P. McHale; John F. Callan; Borivoj Vojnovic; Anne E. Kiltie; Eleanor Stride

doi:10.1016/j.ultrasmedbio.2021.02.001

Evaluation of Loading Strategies to Improve Tumor Uptake of Gemcitabine in a Murine Orthotopic Bladder Cancer Model Using Ultrasound and Microbubbles

Jia Ling Ruan, Richard J. Browning, Yesna O. Yildiz, Luca Bau, Sukanta Kamila, Michael D. Gray, Lisa Folkes, Alix Hampson, Anthony P. McHale, John F. Callan, Borivoj Vojnovic, Anne E. Kiltie, Eleanor Stride^*

^*Corresponding author for this work

The Rowett Institute of Nutrition and Health

Research output: Contribution to journal › Article › peer-review

4 Citations (Scopus)

Abstract

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.

Original language	English
Pages (from-to)	1596-1615
Number of pages	20
Journal	Ultrasound in Medicine and Biology
Volume	47
Issue number	6
Early online date	8 Mar 2021
DOIs	https://doi.org/10.1016/j.ultrasmedbio.2021.02.001
Publication status	Published - 1 Jun 2021

Bibliographical note

Funding 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.

Keywords

Biotinylation
Bladder cancer
Gemcitabine
Liposome
Microbubbles
Nanoparticles
Orthotopic model
Ultrasound-mediated drug delivery

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Ruan, J. L., Browning, R. J., Yildiz, Y. O., Bau, L., Kamila, S., Gray, M. D., Folkes, L., Hampson, A., McHale, A. P., Callan, J. F., Vojnovic, B., Kiltie, A. E., & Stride, E. (2021). Evaluation of Loading Strategies to Improve Tumor Uptake of Gemcitabine in a Murine Orthotopic Bladder Cancer Model Using Ultrasound and Microbubbles. Ultrasound in Medicine and Biology, 47(6), 1596-1615. https://doi.org/10.1016/j.ultrasmedbio.2021.02.001

Ruan, JL, Browning, RJ, Yildiz, YO, Bau, L, Kamila, S, Gray, MD, Folkes, L, Hampson, A, McHale, AP, Callan, JF, Vojnovic, B, Kiltie, AE & Stride, E 2021, 'Evaluation of Loading Strategies to Improve Tumor Uptake of Gemcitabine in a Murine Orthotopic Bladder Cancer Model Using Ultrasound and Microbubbles', Ultrasound in Medicine and Biology, vol. 47, no. 6, pp. 1596-1615. https://doi.org/10.1016/j.ultrasmedbio.2021.02.001

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title = "Evaluation of Loading Strategies to Improve Tumor Uptake of Gemcitabine in a Murine Orthotopic Bladder Cancer Model Using Ultrasound and Microbubbles",

abstract = "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.",

keywords = "Biotinylation, Bladder cancer, Gemcitabine, Liposome, Microbubbles, Nanoparticles, Orthotopic model, Ultrasound-mediated drug delivery",

author = "Ruan, {Jia Ling} and Browning, {Richard J.} and Yildiz, {Yesna O.} and Luca Bau and Sukanta Kamila and Gray, {Michael D.} and Lisa Folkes and Alix Hampson and McHale, {Anthony P.} and Callan, {John F.} and Borivoj Vojnovic and Kiltie, {Anne E.} and Eleanor Stride",

note = "Funding 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. ",

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AU - Browning, Richard J.

AU - Yildiz, Yesna O.

AU - Bau, Luca

AU - Kamila, Sukanta

AU - Gray, Michael D.

AU - Folkes, Lisa

AU - Hampson, Alix

AU - McHale, Anthony P.

AU - Callan, John F.

AU - Vojnovic, Borivoj

AU - Kiltie, Anne E.

AU - Stride, Eleanor

N1 - Funding 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.

PY - 2021/6/1

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N2 - 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.

AB - 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.

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KW - Gemcitabine

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KW - Microbubbles

KW - Nanoparticles

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Evaluation of Loading Strategies to Improve Tumor Uptake of Gemcitabine in a Murine Orthotopic Bladder Cancer Model Using Ultrasound and Microbubbles

Abstract

Bibliographical note

Keywords

UN SDGs

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