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

Abstract

PurposeChemoradiation 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 MethodsCD1-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.ResultsA 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.ConclusionsUltrasound 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.

Highlights

Bladder cancer is the 10th most common cancer worldwide, with approximately 550,000 new cases each year.[1]
At 14 days posttreatment, compared with those in the MB þ US only group, only mice subjected to conventional chemoradiation therapy or ultrasound with gemcitabine conjugated microbubbles and irradiation still showed significant tumor growth delay (Fig. 2a and 2b, P < .05 for each)
One day after treatment, compared with the control, we found a significant weight loss for the 3 ultrasound-mediated drug delivery groups: MB þ US þ IR (4.7 Æ 1.4%, P < .05), gem þ MB þ US þ IR (5.0 Æ 1.1%, P < .05), and gembioMB þ US þ IR (6.6 Æ 1.0%, P < .001) (Fig. E2b)

Summary

Introduction

Bladder cancer is the 10th most common cancer worldwide, with approximately 550,000 new cases each year.[1] Most are urothelial carcinomas, and approximately a quarter of these are muscle-invasive bladder cancer (MIBC) in which cancer spreads into the detrusor muscle of the bladder wall. Gemcitabine-based chemoradiation treatment is widely used, but the toxicity of gemcitabine results in both severe systemic side effects and increased effects of radiation in the healthy bladder tissue surrounding the tumor.[6,7,8] As many MIBC patients are elderly and unable to tolerate these effects,[8] improving the delivery of gemcitabine to the tumor site would allow a larger number of patients to receive concurrent gemcitabine-based chemoradiation therapy for MIBC

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