Intermediate stage atherosclerosis regression using combined methotrexate- mediated ultrasound sonoporation therapy and gold nanoparticles- mediated X- rays- based Auger electron therapy

Abstract

Abstract Background Atherosclerosis is a slow, progressive disease that may begin as early as childhood. Although the exact cause is unknown, atherosclerosis may start with damage or injury to the inner layer of an artery. Atherosclerosis is the main cause of stroke and myocardial infarction. In atherosclerosis, local inflammation and associated macrophage activity can lead to foam cell-rich lesion formation, making inflammation an important therapeutic target in cerebrovascular and cardiovascular diseases. Aims In this study, we developed an experimental pulsed low level focused ultrasound system, and investigated its effectiveness on intermediate stage atherosclerosis regression accompanied by intravenous lipid-based encapsulated methotrexate nanoparticles administration and lipid based encapsulated gold nanoparticles-mediated X-rays-based Auger electron therapy in the golden Syrian hamster common carotid artery, wherein diagnostic B-mode ultrasound is combined with ultrasound therapy system, with a goal of increased safety. Methods In this study, common carotid arteries of hamsters submitted to intermediate stage atherosclerosis using intravascular balloon injury and high-cholesterol diet injury. Then common carotid arteries of the treatment group (n=10) at the injured region, underwent pulsed low level focused ultrasound (F=1.3 MHz, P=24 W, PD=100 ms)-mediated sonoporation therapy accompanied by intravenous lipid-based encapsulated methotrexate nanoparticles (10ml/kg) administration and lipid based encapsulated gold nanoparticles-mediated X-rays (25 Gy)-based Auger electron therapy. Wall mean thickness and percentage of luminal cross-sectional area of stenosis were measured by ultrasonography and histopathology. Results Results from ultrasonography and histopathology showed a significant reduction in the mean value for wall mean thickness, percentage of luminal cross-sectional area of stenosis, lipid-laden cells and lipid droplets density at the stenotic region in the treatment group compared with the other groups (P<0.05) Conclusions Enhanced apoptotic and anti-proliferative effect of methotrexate, induced by enhanced inertial cavitation-based sonoporation effect of focused ultrasound, due to collapsed capsules accompanied by enhanced apoptotic effect of Auger electron therapy, can cause to regress of the intermediate stage atherosclerosis and significantly dilate the luminal cross-sectional area of stenosis. Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): Mehrad Research Lab