Fluorescein-mediated sonodynamic therapy in a rat glioma model

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.

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Abbreviations

HGG:

High-grade Glioma

SDT:

Sonodynamic therapy

ROS:

Reactive oxygen species

PDT:

Photodynamic therapy

5-ALA:

5-Aminolevulinic acid

FUS:

Focused ultrasound

BBB:

Blood–brain barrier

IHC:

Immunohistochemistry

TUNEL:

TdT-mediated dUTP nick end labelling

MRI:

Magnetic resonance imaging

HIFU:

High intensity focused ultrasound

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Funding

This work was conducted at University of Virginia through a grant from the Focused Ultrasound Foundation.

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Correspondence to Francesco Prada.

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Prada, F., Sheybani, N., Franzini, A. et al. Fluorescein-mediated sonodynamic therapy in a rat glioma model. J Neurooncol (2020). https://doi.org/10.1007/s11060-020-03536-2

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Keywords

  • Sonodynamic therapy
  • Fluorescein
  • Focused ultrasound
  • Brain tumor
  • Sonosensitizer
  • Neuro-oncology