Francesco Prada1,2,3, Natasha Sheybani4, Andrea Franzini5,6, David Moore7, Diogo Cordeiro5, Jason Sheehan5, Kelsie Timbie7, Zhiyuan Xu5. 1. Department of Neurological Surgery, University of Virginia Health Science Center, Charlottesville, VA, USA. francesco.prada@istituto-besta.it. 2. Department of Neurosurgery, Fondazione IRCCS Istituto Neurologico C. Besta, Milan, Italy. francesco.prada@istituto-besta.it. 3. Focused Ultrasound Foundation, Charlottesville, VA, USA. francesco.prada@istituto-besta.it. 4. Department of Biomedical Engineering, University of Virginia, Charlottesville, VA, USA. 5. Department of Neurological Surgery, University of Virginia Health Science Center, Charlottesville, VA, USA. 6. Department of Neurosurgery, Fondazione IRCCS Istituto Neurologico C. Besta, Milan, Italy. 7. Focused Ultrasound Foundation, Charlottesville, VA, USA.
Abstract
INTRODUCTION: Malignant gliomas have a dismal prognosis and significant efforts are being made to develop more effective treatments. Sonodynamic therapy (SDT) is an emerging modality for cancer treatment which combines ultrasound with sonosensitizers to produce a localized cytotoxic effect. The aim of this study is to demonstrate the efficacy of SDT with fluorescein (FL) and low-intensity focused ultrasound in inhibiting the growth of ectopic gliomas implanted in the rat's subcutaneous tissue. METHODS: In vivo cytotoxicity of FL-SDT was evaluated in C6 rat glioma cells which were inoculated subcutaneously. Tumor specific extracellular FL extravasation and accumulation was assessed with IVIS imaging in rats receiving systemic FL. Effects of FL-SDT with focused low-intensity ultrasound on tumor growth, and histological features of the rat's tumors were investigated. Treatment related apoptosis and necrosis were analyzed using hematoxylin & eosin, and apoptosis-specific staining. RESULTS: IVIS imaging revealed a high degree of FL accumulation within the tumor, with a nearly threefold increase in tumoral epifluorescence signal over background. SDT significantly inhibited outgrowth of ectopic C6 gliomas across all three FUS exposure conditions. TUNEL and active caspase-3 staining did not reveal conclusive trends across control and SDT condition for apoptosis. CONCLUSION: Our results suggest that SDT with FL and low-intensity FUS is effective in inhibiting the growth of ectopic malignant gliomas in rats. The selective FL extravasation and accumulation in the tumor areas where the blood-brain barrier is damaged suggests the tumor-specificity of the treatment. The possibility to use this treatment in intracranial models and in human gliomas will have to be explored in further studies.
INTRODUCTION: Malignant gliomas have a dismal prognosis and significant efforts are being made to develop more effective treatments. Sonodynamic therapy (SDT) is an emerging modality for cancer treatment which combines ultrasound with sonosensitizers to produce a localized cytotoxic effect. The aim of this study is to demonstrate the efficacy of SDT with fluorescein (FL) and low-intensity focused ultrasound in inhibiting the growth of ectopic gliomas implanted in the rat's subcutaneous tissue. METHODS: In vivo cytotoxicity of FL-SDT was evaluated in C6 rat glioma cells which were inoculated subcutaneously. Tumor specific extracellular FL extravasation and accumulation was assessed with IVIS imaging in rats receiving systemic FL. Effects of FL-SDT with focused low-intensity ultrasound on tumor growth, and histological features of the rat's tumors were investigated. Treatment related apoptosis and necrosis were analyzed using hematoxylin & eosin, and apoptosis-specific staining. RESULTS: IVIS imaging revealed a high degree of FL accumulation within the tumor, with a nearly threefold increase in tumoral epifluorescence signal over background. SDT significantly inhibited outgrowth of ectopic C6 gliomas across all three FUS exposure conditions. TUNEL and active caspase-3 staining did not reveal conclusive trends across control and SDT condition for apoptosis. CONCLUSION: Our results suggest that SDT with FL and low-intensity FUS is effective in inhibiting the growth of ectopic malignant gliomas in rats. The selective FL extravasation and accumulation in the tumor areas where the blood-brain barrier is damaged suggests the tumor-specificity of the treatment. The possibility to use this treatment in intracranial models and in human gliomas will have to be explored in further studies.
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