Sonodynamic Therapy: Porphyrin-Based Sensitizers and Low-Intensity Ultrasound for Precision Treatment of Glioblastoma

Abstract

Sonodynamic treatment (SDT) is also beginning to be of interest as an effective noninvasive approach to treat glioblastoma multiforme, in which ultrasonically triggered sensitizers generate an effector of cytotoxic reactive oxygen species (ROS). The current research determined the competence of three structurally novel porphyrin-based sensitizers (named as P1, P2, and P3) under the arm of low-intensity pulsed ultrasound (LIPUS) as an agent that enhances ROS-mediated apoptosis in the cells of the glioma. The authors tested the model of U87-MG human glioblastoma cell cultures under the treatment with porphyrins at the concentration of 27 M down to 10.7 M with and without LIPUS treatment (1 MHz, 1.0W/cm², 50% duty cycle, 5 min). The effects of the combined porphyrin and LIPUS treatment were also more likely to show effects of increased production of ROS in all of its concentrations compared with monotherapies or control, which was not treated. P3 + LIPUS yielded the highest amount of ROS, with the number increasing 3.2 0.4 times more than control (p < 0.001). To compare, the percentage of apoptosis increased to 46.7% relative to the 8.6% of the untreated cells using the combined SDT (adjusted odds ratio [aOR] = 6.9; 95% confidence interval [CI]: 3.21–5.0). Porphyrin and ultrasound also had a synergistic effect with all the sensitizers and P3 represented the highest synergy index. The multivariate regression analysis showed that interaction between light concentration of sensitizer and the parameters of ultrasound exposure had a statistical significance (p < 0.01) such that it was possible to state that there was upregulated oxidative stress with dual-modality treatment. The findings clearly confirm that a mixture of LIPUS and newly identified porphyrin-based sensitizers is more effective in promoting the intracellular concentration of ROS and triggering an apoptosis in glioma cells than either of the two groups. This synergy has been observed in preclinical studies that are underway on the further development of such a process in the treatment of gliomas. The results are already included in a growing collection of literature on the potential SDT overcoming the disadvantages that are associated with the traditional photodynamic therapy to chemoresistance in gliomas. Besides determining the efficacy of P3, this study provides the requisite quantitative biomarkers and synergy models, which may be implemented to construct intelligent and closed-loop SDT systems. The results form the basis of the quantitative development of adaptive, closed-loop SDT systems in the future.