Intracranial Sonodynamic Therapy With 5-Aminolevulinic Acid and Sodium Fluorescein: Safety Study in a Porcine Model

Abstract

BackgroundSonodynamic therapy (SDT) is an emerging ultrasound-based treatment modality for malignant gliomas which combines ultrasound with sonosensitizers to produce a localized cytotoxic and modulatory effect. Tumor-specificity of the treatment is achieved by the selective extravasation and accumulation of sonosensitizers in the tumor-bearing regions. The aim of this study is to demonstrate the safety of low-intensity ultrasonic irradiation of healthy brain tissue after the administration of FDA-approved sonosensitizers used for SDT in experimental studies in an in vivo large animal model.MethodsIn vivo safety of fluorescein (Na-Fl)- and 5 aminolevulinic acid (5-ALA)-mediated low-intensity ultrasound irradiation of healthy brain parenchyma was assessed in two sets of four healthy swine brains, using the magnetic resonance imaging (MRI)-guided Insightec ExAblate 4000 220 kHz system. After administration of the sonosensitizers, a wide fronto-parietal craniotomy was performed in pig skulls to allow transmission of ultrasonic beams. Sonication was performed on different spots within the thalamus and periventricular white matter with continuous thermal monitoring. Sonication-related effects were investigated with MRI and histological analysis.ResultsPost-treatment MRI images acquired within one hour following the last sonication, on day one, and day seven did not visualize any sign of brain damage. On histopathology, no signs of necrosis or apoptosis attributable to the ultrasonic treatments were shown in target areas.ConclusionsThe results of the present study suggest that either Na-FL or 5-ALA-mediated sonodynamic therapies under MRI-guidance with the current acoustic parameters are safe towards healthy brain tissue in a large in vivo model. These results further support growing interest in clinical translation of sonodynamic therapy for intracranial gliomas and other brain tumors.

From Focused Ultrasound Tumor Ablation to Brain Blood Barrier Opening for High Grade Glioma: A Systematic Review

“…The measurement is made with Cleaved Caspase-3, MIB-1 level, GammaH2Ax in surgical specimen tissue. Another prospective study to be conducted at Besta Institute in Milan will evaluate the safety and feasibility of sonodynamic therapy with 5-ALA in patients with newly diagnosed GBM [ 53 , 54 , 55 ].…”

“…The measurement is made with Cleaved Caspase-3, MIB-1 level, Gamma-H2Ax in surgical specimen tissue. Another prospective study to be conducted at Besta Institute in Milan will evaluate the safety and feasibility of sonodynamic therapy with 5-ALA in patients with newly diagnosed GBM [53][54][55]. Sunnybrook Health Sciences Centre in Toronto is leading three different trials on tumor ablation, BBB opening and Carboplatin delivery through BBB (NCT01473485; NCT03616860; NCT04440358).…”

Past, present and future of Focused Ultrasound as an adjunct or complement to DIPG/DMG therapy: A consensus of the 2021 FUSF DIPG meeting

“…The cytotoxic reaction only occurs when FUS is combined with a sonosensitizer and neither FUS nor the sonosensitizer alone is capable of inducing cell death individually [35] . The safety of this technique has been validated in a large animal preclinical study [36] and clinical trials of SDT combined with 5-ALA are now underway (NCT05370578, NCT04845919, NCT05123534).…”

Sonodynamic therapy and Magnetic Resonance-guided Focused Ultrasound: new therapeutic strategy in Glioblastoma

“…'In vivo' studies used an animal model to verify the feasibility of this technique: more than investigating just the anti-tumoral effect of STD, these studies prove the safety of SDT towards healthy brain tissue [33,45].…”