Early stage atherosclerosis regression using combined sonotherapy and mitoxantrone-mediated sonoporation therapy

Abstract Background In atherosclerosis, local inflammation and associated macrophage activity can lead to foam cell-rich plaque formation, which results to plaque rupture and thrombosis, making inflammation an important therapeutic target in cardiovascular disease. The early stage of atherosclerosis is characterized by the accumulation of low-density lipoprotein (LDL) droplets, leading to the creation of foam cells. Foam cells are generated by uncontrolled uptake of modified LDL, especially oxidized LDL (oxLDL). Purpose In this study, we developed an experimental focused ultrasound-based combined sonotherapy and sonoporation therapy system, and investigated its effectiveness on macrophage-derived foam cells reduction, wherein a high resolution diagnostic ultrasound is adjuncted with combination therapy system, with a goal of increased safety. Methods Briefly, New Zealand white rabbits underwent primary balloon dilatation injury at the right common carotid artery followed by a 1.5% cholesterol-rich diet injury for three weeks. Histopathology results showed the early stage atherosclerosis formation in all of the rabbits' arteries. Then common carotid arteries of the treatment group at the lesion region, treated using extracorporeal low-level pulsed-focused ultrasound (P=11 W, F=1.1 MHz, DF=50%) sonotherapy accompanied by mitoxantrone-loaded PESDA (Perfluorocarbon-Exposed Sonicated Dextrose Albumin) microbubbles (100 ml/kg, 2–5x105 bubbles/ml)-mediated sonoporation therapy. Foam cells density were evaluated in the treatment group compared with the other groups using B-mode ultrasonography and histopathology. Results Results from B-mode ultrasonography and histopathology showed a significant reduction in the mean value for immune cells and foam cells density within the early stage atherosclerotic lesion in the treatment group compared with the other groups (p<0.05). Conclusion Enhanced sonoporation effect of ultrasound, induced by collapsed PESDA microbubbles accompanied by anti-inflammatory effect of sonotherapy and antineoplastic and cytotoxic effect of mitoxantrone can cause to reduce the immune cells and foam cells density within the lesion. These finding provide the basis for developing low-level pulsed-focused ultrasound-based combined sonotherapy and sonoporation therapy for a successful clinical application in the treatment of the early stage atherosclerosis. Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): Mehrad Research Lab