Ultrasound-Mediated Gemcitabine Delivery Reduces the Normal-Tissue Toxicity of Chemoradiation Therapy in a Muscle-Invasive Bladder Cancer Model

Jia Ling Ruan; Richard J. Browning; Yesna O. Yildiz; Michael Gray; Luca Bau; Sukanta Kamila; James Thompson; Amy Elliott; Sean Smart; Anthony P. McHale; John F. Callan; Borivoj Vojnovic; Eleanor Stride; Anne E. Kiltie

doi:10.1016/j.ijrobp.2020.11.046

Ultrasound-Mediated Gemcitabine Delivery Reduces the Normal-Tissue Toxicity of Chemoradiation Therapy in a Muscle-Invasive Bladder Cancer Model

Jia Ling Ruan, Richard J. Browning, Yesna O. Yildiz, Michael Gray, Luca Bau, Sukanta Kamila, James Thompson, Amy Elliott, Sean Smart, Anthony P. McHale, John F. Callan, Borivoj Vojnovic, Eleanor Stride, Anne E. Kiltie^*

^*Corresponding author for this work

The Rowett Institute of Nutrition and Health

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Abstract

Purpose: Chemoradiation therapy is the standard of care in muscle-invasive bladder cancer (MIBC). Although agents such as gemcitabine can enhance tumor radiosensitivity, their side effects can limit patient eligibility and treatment efficacy. This study investigates ultrasound and microbubbles for targeting gemcitabine delivery to reduce normal-tissue toxicity in a murine orthotopic MIBC model. Materials and Methods: CD1-nude mice were injected orthotopically with RT112 bladder tumor cells. Conventional chemoradiation involved injecting gemcitabine (10 mg/kg) before 6 Gy targeted irradiation of the bladder area using the Small Animal Radiation Research Platform (SARRP). Ultrasound-mediated gemcitabine delivery (10 mg/kg gemcitabine) involved either coadministration of microbubbles with gemcitabine or conjugating gemcitabine onto microbubbles followed by exposure to ultrasound (1.1 MHz center frequency, 1 MPa peak negative pressure, 1% duty cycle, and 0.5 Hz pulse repetition frequency) before SARRP irradiation. The effect of ultrasound and microbubbles alone was also tested. Tumor volumes were measured by 3D ultrasound imaging. Acute normal-tissue toxicity from 12 Gy to the lower bowel area was assessed using an intestinal crypt assay in mice culled 3.75 days posttreatment. Results: A significant delay in tumor growth was observed with conventional chemoradiation therapy and both microbubble groups (P < .05 compared with the radiation-only group). Transient weight loss was seen in the microbubble groups, which resolved within 10 days posttreatment. A positive correlation was found between weight loss on day 3 posttreatment and tumor growth delay (P < .05; R² = 0.76). In contrast with conventional chemoradiation therapy, ultrasound-mediated drug delivery methods did not exacerbate the acute intestinal toxicity using the crypt assay. Conclusions: Ultrasound and microbubbles offer a promising new approach for improving chemoradiation therapy for muscle-invasive bladder cancer, maintaining a delay in tumor growth but with reduced acute intestinal toxicity compared with conventional chemoradiation therapy.

Original language	English
Pages (from-to)	1472-1482
Number of pages	11
Journal	International Journal of Radiation Oncology Biology Physics
Volume	109
Issue number	5
DOIs	https://doi.org/10.1016/j.ijrobp.2020.11.046
Publication status	Published - 1 Apr 2021

Bibliographical note

Acknowledgmentsd: We thank the Cancer Research UK and the Engineering and Physical Sciences Research Council for the funding support of this work. We thank staff of the IBME mechanical workshop (Mr James Fisk and Mr David Salisbury) for assistance with development of the ultrasound jigs. We also thank Ms Karla Watson and Magdalena Hutchins of the Oncology Biomedical Science Unit for assistance with animal maintenance.

Funding Information:
This work was funded by a Cancer Research UK Multidisciplinary Project Award (C15140/A19817, to B.V., E.S., and A.E.K.) and grant EP/L024012/1 from the Engineering and Physical Sciences Research Council (to E.S. for M.G. and L.B.).

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Ruan, J. L., Browning, R. J., Yildiz, Y. O., Gray, M., Bau, L., Kamila, S., Thompson, J., Elliott, A., Smart, S., McHale, A. P., Callan, J. F., Vojnovic, B., Stride, E., & Kiltie, A. E. (2021). Ultrasound-Mediated Gemcitabine Delivery Reduces the Normal-Tissue Toxicity of Chemoradiation Therapy in a Muscle-Invasive Bladder Cancer Model. International Journal of Radiation Oncology Biology Physics, 109(5), 1472-1482. https://doi.org/10.1016/j.ijrobp.2020.11.046

Ultrasound-Mediated Gemcitabine Delivery Reduces the Normal-Tissue Toxicity of Chemoradiation Therapy in a Muscle-Invasive Bladder Cancer Model. / Ruan, Jia Ling; Browning, Richard J.; Yildiz, Yesna O. et al.
In: International Journal of Radiation Oncology Biology Physics, Vol. 109, No. 5, 01.04.2021, p. 1472-1482.

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

Ruan, JL, Browning, RJ, Yildiz, YO, Gray, M, Bau, L, Kamila, S, Thompson, J, Elliott, A, Smart, S, McHale, AP, Callan, JF, Vojnovic, B, Stride, E & Kiltie, AE 2021, 'Ultrasound-Mediated Gemcitabine Delivery Reduces the Normal-Tissue Toxicity of Chemoradiation Therapy in a Muscle-Invasive Bladder Cancer Model', International Journal of Radiation Oncology Biology Physics, vol. 109, no. 5, pp. 1472-1482. https://doi.org/10.1016/j.ijrobp.2020.11.046

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title = "Ultrasound-Mediated Gemcitabine Delivery Reduces the Normal-Tissue Toxicity of Chemoradiation Therapy in a Muscle-Invasive Bladder Cancer Model",

abstract = "Purpose: Chemoradiation therapy is the standard of care in muscle-invasive bladder cancer (MIBC). Although agents such as gemcitabine can enhance tumor radiosensitivity, their side effects can limit patient eligibility and treatment efficacy. This study investigates ultrasound and microbubbles for targeting gemcitabine delivery to reduce normal-tissue toxicity in a murine orthotopic MIBC model. Materials and Methods: CD1-nude mice were injected orthotopically with RT112 bladder tumor cells. Conventional chemoradiation involved injecting gemcitabine (10 mg/kg) before 6 Gy targeted irradiation of the bladder area using the Small Animal Radiation Research Platform (SARRP). Ultrasound-mediated gemcitabine delivery (10 mg/kg gemcitabine) involved either coadministration of microbubbles with gemcitabine or conjugating gemcitabine onto microbubbles followed by exposure to ultrasound (1.1 MHz center frequency, 1 MPa peak negative pressure, 1% duty cycle, and 0.5 Hz pulse repetition frequency) before SARRP irradiation. The effect of ultrasound and microbubbles alone was also tested. Tumor volumes were measured by 3D ultrasound imaging. Acute normal-tissue toxicity from 12 Gy to the lower bowel area was assessed using an intestinal crypt assay in mice culled 3.75 days posttreatment. Results: A significant delay in tumor growth was observed with conventional chemoradiation therapy and both microbubble groups (P < .05 compared with the radiation-only group). Transient weight loss was seen in the microbubble groups, which resolved within 10 days posttreatment. A positive correlation was found between weight loss on day 3 posttreatment and tumor growth delay (P < .05; R2 = 0.76). In contrast with conventional chemoradiation therapy, ultrasound-mediated drug delivery methods did not exacerbate the acute intestinal toxicity using the crypt assay. Conclusions: Ultrasound and microbubbles offer a promising new approach for improving chemoradiation therapy for muscle-invasive bladder cancer, maintaining a delay in tumor growth but with reduced acute intestinal toxicity compared with conventional chemoradiation therapy.",

author = "Ruan, {Jia Ling} and Browning, {Richard J.} and Yildiz, {Yesna O.} and Michael Gray and Luca Bau and Sukanta Kamila and James Thompson and Amy Elliott and Sean Smart and McHale, {Anthony P.} and Callan, {John F.} and Borivoj Vojnovic and Eleanor Stride and Kiltie, {Anne E.}",

note = "Acknowledgmentsd: We thank the Cancer Research UK and the Engineering and Physical Sciences Research Council for the funding support of this work. We thank staff of the IBME mechanical workshop (Mr James Fisk and Mr David Salisbury) for assistance with development of the ultrasound jigs. We also thank Ms Karla Watson and Magdalena Hutchins of the Oncology Biomedical Science Unit for assistance with animal maintenance. Funding Information: This work was funded by a Cancer Research UK Multidisciplinary Project Award (C15140/A19817, to B.V., E.S., and A.E.K.) and grant EP/L024012/1 from the Engineering and Physical Sciences Research Council (to E.S. for M.G. and L.B.). ",

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T1 - Ultrasound-Mediated Gemcitabine Delivery Reduces the Normal-Tissue Toxicity of Chemoradiation Therapy in a Muscle-Invasive Bladder Cancer Model

AU - Ruan, Jia Ling

AU - Browning, Richard J.

AU - Yildiz, Yesna O.

AU - Gray, Michael

AU - Bau, Luca

AU - Kamila, Sukanta

AU - Thompson, James

AU - Elliott, Amy

AU - Smart, Sean

AU - McHale, Anthony P.

AU - Callan, John F.

AU - Vojnovic, Borivoj

AU - Stride, Eleanor

AU - Kiltie, Anne E.

N1 - Acknowledgmentsd: We thank the Cancer Research UK and the Engineering and Physical Sciences Research Council for the funding support of this work. We thank staff of the IBME mechanical workshop (Mr James Fisk and Mr David Salisbury) for assistance with development of the ultrasound jigs. We also thank Ms Karla Watson and Magdalena Hutchins of the Oncology Biomedical Science Unit for assistance with animal maintenance. Funding Information: This work was funded by a Cancer Research UK Multidisciplinary Project Award (C15140/A19817, to B.V., E.S., and A.E.K.) and grant EP/L024012/1 from the Engineering and Physical Sciences Research Council (to E.S. for M.G. and L.B.).

PY - 2021/4/1

Y1 - 2021/4/1

N2 - Purpose: Chemoradiation therapy is the standard of care in muscle-invasive bladder cancer (MIBC). Although agents such as gemcitabine can enhance tumor radiosensitivity, their side effects can limit patient eligibility and treatment efficacy. This study investigates ultrasound and microbubbles for targeting gemcitabine delivery to reduce normal-tissue toxicity in a murine orthotopic MIBC model. Materials and Methods: CD1-nude mice were injected orthotopically with RT112 bladder tumor cells. Conventional chemoradiation involved injecting gemcitabine (10 mg/kg) before 6 Gy targeted irradiation of the bladder area using the Small Animal Radiation Research Platform (SARRP). Ultrasound-mediated gemcitabine delivery (10 mg/kg gemcitabine) involved either coadministration of microbubbles with gemcitabine or conjugating gemcitabine onto microbubbles followed by exposure to ultrasound (1.1 MHz center frequency, 1 MPa peak negative pressure, 1% duty cycle, and 0.5 Hz pulse repetition frequency) before SARRP irradiation. The effect of ultrasound and microbubbles alone was also tested. Tumor volumes were measured by 3D ultrasound imaging. Acute normal-tissue toxicity from 12 Gy to the lower bowel area was assessed using an intestinal crypt assay in mice culled 3.75 days posttreatment. Results: A significant delay in tumor growth was observed with conventional chemoradiation therapy and both microbubble groups (P < .05 compared with the radiation-only group). Transient weight loss was seen in the microbubble groups, which resolved within 10 days posttreatment. A positive correlation was found between weight loss on day 3 posttreatment and tumor growth delay (P < .05; R2 = 0.76). In contrast with conventional chemoradiation therapy, ultrasound-mediated drug delivery methods did not exacerbate the acute intestinal toxicity using the crypt assay. Conclusions: Ultrasound and microbubbles offer a promising new approach for improving chemoradiation therapy for muscle-invasive bladder cancer, maintaining a delay in tumor growth but with reduced acute intestinal toxicity compared with conventional chemoradiation therapy.

AB - Purpose: Chemoradiation therapy is the standard of care in muscle-invasive bladder cancer (MIBC). Although agents such as gemcitabine can enhance tumor radiosensitivity, their side effects can limit patient eligibility and treatment efficacy. This study investigates ultrasound and microbubbles for targeting gemcitabine delivery to reduce normal-tissue toxicity in a murine orthotopic MIBC model. Materials and Methods: CD1-nude mice were injected orthotopically with RT112 bladder tumor cells. Conventional chemoradiation involved injecting gemcitabine (10 mg/kg) before 6 Gy targeted irradiation of the bladder area using the Small Animal Radiation Research Platform (SARRP). Ultrasound-mediated gemcitabine delivery (10 mg/kg gemcitabine) involved either coadministration of microbubbles with gemcitabine or conjugating gemcitabine onto microbubbles followed by exposure to ultrasound (1.1 MHz center frequency, 1 MPa peak negative pressure, 1% duty cycle, and 0.5 Hz pulse repetition frequency) before SARRP irradiation. The effect of ultrasound and microbubbles alone was also tested. Tumor volumes were measured by 3D ultrasound imaging. Acute normal-tissue toxicity from 12 Gy to the lower bowel area was assessed using an intestinal crypt assay in mice culled 3.75 days posttreatment. Results: A significant delay in tumor growth was observed with conventional chemoradiation therapy and both microbubble groups (P < .05 compared with the radiation-only group). Transient weight loss was seen in the microbubble groups, which resolved within 10 days posttreatment. A positive correlation was found between weight loss on day 3 posttreatment and tumor growth delay (P < .05; R2 = 0.76). In contrast with conventional chemoradiation therapy, ultrasound-mediated drug delivery methods did not exacerbate the acute intestinal toxicity using the crypt assay. Conclusions: Ultrasound and microbubbles offer a promising new approach for improving chemoradiation therapy for muscle-invasive bladder cancer, maintaining a delay in tumor growth but with reduced acute intestinal toxicity compared with conventional chemoradiation therapy.

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Ultrasound-Mediated Gemcitabine Delivery Reduces the Normal-Tissue Toxicity of Chemoradiation Therapy in a Muscle-Invasive Bladder Cancer Model

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