Ultrasound-stimulated microbubble radiation enhancement of tumors: Single-dose and fractionated treatment evaluation.

Evan Mcnabb,Christine Tarapacki,Niki Law,Azza Al-Mahrouki,Gregory J Czarnota,Farah Hussein,Scott Mckay,Irina V Lebedeva

doi:10.1371/journal.pone.0239456

Abstract

The use of ultrasound-stimulated microbubble therapy has successfully been used to target tumor vasculature and enhance the effects of radiation therapy in tumor xenografts in mice. Here, we further investigate this treatment using larger, more clinically relevant tumor models. New Zealand white rabbits bearing prostate tumor (PC3) xenografts received a single treatment of either ultrasound-stimulated microbubbles (USMB), ionizing radiation (XRT; 8Gy), or a combination of both treatments (USMB+XRT). Treatment outcome was evaluated 24 hours after treatment using histopathology, immunolabeling, 3D Doppler ultrasound and photoacoustic imaging. A second cohort of rabbits received multiple treatments over a period of three weeks, where USMB treatments were delivered twice weekly with daily XRT treatments to deliver a fractionated 2Gy dose five days per week. A significant decrease in vascular function, observed through immunolabeling of vascular endothelial cells, was observed in tumors receiving the combined treatment (USMB+XRT) compared to control and single treatment groups. This was associated with an increase in cell death as observed through in situ end labeling (ISEL), a decrease in vascular index measured by Power Doppler imaging, and a decrease in oxygen saturation. In rabbits undergoing the long-term fractionated combined treatment, a significant growth delay was observed after 1 week and a significant reduction in tumor size was observed after 3 weeks with combined therapy. Results demonstrated an enhancement of radiation effect and superior anti-tumor effect of the combination of USMB+XRT compared to the single treatments alone. Tumor growth was maximally inhibited with fractionated radiotherapy combined with the ultrasound-stimulated microbubble-based therapy.

Highlights

Half of cancers are treated with radiation therapy in their management and extensively in the treatment of breast, head and neck, lung and prostate cancers [1,2,3]
The cell membrane effect sensitizes the endothelial cells to radiation treatment through a membraneactivated, ceramide-mediated cell death pathway that would otherwise only be activated at very high single doses of radiation, i.e., > 10 Gy [26,27,28]
Results indicated that the combination of ultrasound-stimulated microbubble therapy (USMB) treatment and radiation resulted in enhanced tumor cell kill and vascular disruption

Summary

Introduction

Half of cancers are treated with radiation therapy in their management and extensively in the treatment of breast, head and neck, lung and prostate cancers [1,2,3]. In order to improve its efficacy, radiation therapy is often administered in combination with other treatments to increase radiosensitivity, for example in conjunction with chemotherapy, nanoparticles, and molecular-targeted therapies [15,16,17,18,19,20]. These often introduce systemic effects, often leading to difficulty in targeting the local tumor microenvironment. Recent investigators have developed a novel and effective combined treatment approach where intravenous microbubbles are stimulated using ultrasound waves to perturb the tumor vascular endothelial cells resulting in enhanced effects of radiation [21, 22]. The cell membrane effect sensitizes the endothelial cells to radiation treatment through a membraneactivated, ceramide-mediated cell death pathway that would otherwise only be activated at very high single doses of radiation, i.e., > 10 Gy [26,27,28]

Methods

Results

Conclusion