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

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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; R 2 = 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 languageEnglish
Pages (from-to)1472-1482
Number of pages11
JournalInternational Journal of Radiation Oncology - Biology - Physics
Volume109
Issue number5
Early online date11 Mar 2021
DOIs
Publication statusPublished - 1 Apr 2021

Bibliographical note

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.).

Funding Information:
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.

Publisher Copyright:
© 2020 The Author(s)

Copyright:
Copyright 2021 Elsevier B.V., All rights reserved.

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