Breast tumor response to ultrasound mediated excitation of microbubbles and radiation therapy in vivo

Lai, Patrick F.H.; Tarapacki, Christine; Tran, William T.; Kaffas, Ahmed El; Lee, Justin; Hupple, Clinton; Iradji, Sarah; Giles, Anoja; Al‐Mahrouki, Azza; Czarnota, Gregory J.

doi:10.18632/oncoscience.299

Cited by 52 publications

(66 citation statements)

References 43 publications

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“…Treatments involving multiple fractions of combined therapy had more apparent arrest of tumor growth and survival using rabbit death and human-modified endpoints and was the only treatment group to demonstrate a trend in where there was arrested tumor growth after 3 weeks (Fig 4). The surviving fraction from combined treatments was similar in comparison to previous observations in PC-3 and MDA-MB-231 tumor bearing mice after 21 days that received lower fractionated doses [21,42], though our results indicate the twice-weekly USMB exposure alone had less effect. The difference in tumor size compared to the mouse model likely plays a role in the decreased induction of endothelial cell damage caused by the USMB treatment, as the acoustic field was applied uniformly towards the more superficial area of the tumor.…”

Section: Plos Onesupporting

confidence: 87%

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

et al. 2020

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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.

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Section: Plos Onesupporting

confidence: 87%

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

et al. 2020

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“…hours after exposure. A similar synergistic enhancement of radiation therapy was observed in bladder [37] and breast [38] xenograft experiments when USMB treatment was used in combination with radiotherapy. These studies demonstrated the mechanism of action for this synergy to be microbubble-induced ceramide-facilitated endothelial cell death.…”

Section: Plos Onesupporting

confidence: 68%

“…vivo in multiple cell lines [15,28,[36][37][38]. Czarnota et al demonstrated that USMB treatment followed by subsequent radiation exposure (2 Gy or 8 Gy) resulted in a synergistic cell death effect in prostate cancer mouse xenografts.…”

Section: Plos Onementioning

confidence: 99%

Optimization of microbubble enhancement of hyperthermia for cancer therapy in an in vivo breast tumour model

et al. 2020

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We have demonstrated that exposing human breast tumour xenografts to ultrasound-stimulated microbubbles enhances tumour cell death and vascular disruption resulting from hyperthermia treatment. The aim of this study was to investigate the effect of varying the hyperthermia and ultrasound-stimulated microbubbles treatment parameters in order to optimize treatment bioeffects. Human breast cancer (MDA-MB-231) tumour xenografts in severe combined immunodeficiency (SCID) mice were exposed to varying microbubble concentrations (0%, 0.1%, 1% or 3% v/v) and ultrasound sonication durations (0, 1, 3 or 5 min) at 570 kPa peak negative pressure and central frequency of 500 kHz. Five hours later, tumours were immersed in a 43˚C water bath for varying hyperthermia treatment durations (0, 10, 20, 30, 40, 50 or 60 minutes). Results indicated a significant increase in tumour cell death reaching 64 ± 5% with combined treatment compared to 11 ± 3% and 26 ± 5% for untreated and USMB-only treated tumours, respectively. A similar but opposite trend was observed in the vascular density of the tumours receiving the combined treatment. Optimal treatment parameters were found to consist of 40 minutes of heat with low power ultrasound treatment microbubble parameters of 1 minute of sonification and a 1% microbubble concentration.

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“…11 Studies have demonstrated that USMBs are effective radioenhancement agents for a variety of cell types in vivo, such as breast, prostate, leukemia, and sarcoma tumors, 15 with additive-to-synergistic effects seen for combinations of USMBs and XRT. 12,15,16 There is evidence to suggest that USMB-mediated radioenhancement results from an endothelial cell insult in the tumor vasculature. Specifically, microbubble excitation initiates apoptosis, likely by inducing sphingomyelinases on the cell surface and subsequently provoking the ceramide pathway.…”

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confidence: 99%

“…Preclinical studies have demonstrated antitumor effects both with USMBs alone 14 and combining USMBs with external beam radiotherapy (XRT) to achieve synergistic effects 11 . Studies have demonstrated that USMBs are effective radioenhancement agents for a variety of cell types in vivo, such as breast, prostate, leukemia, and sarcoma tumors, 15 with additive‐to‐synergistic effects seen for combinations of USMBs and XRT 12,15,16 . There is evidence to suggest that USMB‐mediated radioenhancement results from an endothelial cell insult in the tumor vasculature.…”

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Effect of Treatment Sequencing on the Tumor Response to Combined Treatment With Ultrasound‐Stimulated Microbubbles and Radiotherapy

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Lai

et al. 2020

J of Ultrasound Medicine

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Objectives-To investigate whether timing and sequencing of ultrasoundstimulated microbubbles (USMBs) and external beam radiotherapy (XRT) affect the treatment response in a preclinical prostate cancer model. Methods-Prostate cancer xenografts were treated with ultrasound-stimulated lipid microspheres before and after 8-Gy XRT. Treatments were separated by 0, 3, 6, 12, and 24 hours, with 5 tumors per group. Tumor effects were evaluated by microvessel density (measured by CD31 staining), cell death (terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end-labeling and hematoxylin-eosin staining), and hypoxia (carbonic anhydrase 9 staining). Results-Administering USMBs 6 hours before XRT showed the maximum treatment effect using all 3 assays. At this time, the mean cell death index ± SD was 36% ± 10%, compared with 19% ± 4% for no separation between USMB treatment and XRT; the microvessel density was 9 ± 3 counts per field (19 ± 5 without separation); and the percentage of hypoxic cells was 10% ± 5% (21% ± 4%). The observed treatment effect was greater with USMBs before XRT than when administering XRT first, but these differences were not statistically significant. Conclusions-The maximum tumor effect was observed with USMBs delivered 6 hours before XRT. The sequencing of treatment did not have a significant effect on the tumor response.

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Breast tumor response to ultrasound mediated excitation of microbubbles and radiation therapy in vivo

Cited by 52 publications

References 43 publications

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

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

Optimization of microbubble enhancement of hyperthermia for cancer therapy in an in vivo breast tumour model

Effect of Treatment Sequencing on the Tumor Response to Combined Treatment With Ultrasound‐Stimulated Microbubbles and Radiotherapy

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