title: Quantitative ultrasound characterization of tumor cell death: ultrasound-stimulated microbubbles for radiation enhancement.
abstract: The aim of this study was to assess the efficacy of quantitative ultrasound imaging in characterizing cancer cell death caused by enhanced radiation treatments. This investigation focused on developing this ultrasound modality as an imaging-based non-invasive method that can be used to monitor therapeutic ultrasound and radiation effects. High-frequency (25 MHz) ultrasound was used to image tumor responses caused by ultrasound-stimulated microbubbles in combination with radiation. Human prostate xenografts grown in severe combined immunodeficiency (SCID) mice were treated using 8, 80, or 1000 µL/kg of microbubbles stimulated with ultrasound at 250, 570, or 750 kPa, and exposed to 0, 2, or 8 Gy of radiation. Tumors were imaged prior to treatment and 24 hours after treatment. Spectral analysis of images acquired from treated tumors revealed overall increases in ultrasound backscatter intensity and the spectral intercept parameter. The increase in backscatter intensity compared to the control ranged from 1.9±1.6 dB for the clinical imaging dose of microbubbles (8 µL/kg, 250 kPa, 2 Gy) to 7.0±4.1 dB for the most extreme treatment condition (1000 µL/kg, 750 kPa, 8 Gy). In parallel, in situ end-labelling (ISEL) staining, ceramide, and cyclophilin A staining demonstrated increases in cell death due to DNA fragmentation, ceramide-mediated apoptosis, and release of cyclophilin A as a result of cell membrane permeabilization, respectively. Quantitative ultrasound results indicated changes that paralleled increases in cell death observed from histology analyses supporting its use for non-invasive monitoring of cancer treatment outcomes.
authors: Department of Physical Sciences, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada; Department of Radiation Oncology, Odette Cancer Centre, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada.
authors: Hyunjung Christina
authors: HC
authors: Kim
authors: Department of Physical Sciences, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada; Department of Radiation Oncology, Odette Cancer Centre, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada.
authors: Azza
authors: A
authors: Al-Mahrouki
authors: Department of Medical Biophysics, Faculty of Medicine, University of Toronto, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada.
authors: Alborz
authors: A
authors: Gorjizadeh
authors: Department of Physical Sciences, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada; Department of Radiation Oncology, Odette Cancer Centre, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada; Department of Medical Biophysics, Faculty of Medicine, University of Toronto, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada; Department of Radiation Oncology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
authors: Ali
authors: A
authors: Sadeghi-Naini
authors: Department of Physics, Ryerson University, Toronto, Ontario, Canada.
authors: Raffi
authors: R
authors: Karshafian
authors: Department of Physical Sciences, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada; Department of Radiation Oncology, Odette Cancer Centre, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada; Department of Medical Biophysics, Faculty of Medicine, University of Toronto, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada; Department of Radiation Oncology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada; Department of Physics, Ryerson University, Toronto, Ontario, Canada.
authors: Gregory J
authors: GJ
authors: Czarnota
mesh_terms: D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D002518:Ceramides / Q000494:pharmacology; D053938:DNA Fragmentation; D006801:Humans; D008297:Male; D016513:Mice, SCID; D045423:Microbubbles; D011471:Prostatic Neoplasms / Q000000981:diagnostic imaging / Q000532:radiotherapy*; D011836:Radiation Tolerance; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology; D013016:Sound; D014463:Ultrasonography; D023041:Xenograft Model Antitumor Assays
chemical_list: D002518:Ceramides; D011838:Radiation-Sensitizing Agents