Neointimal hyperplasia regression using combined paclitaxel- mediated confocal dual pulse shock wave sonoporation therapy and catheter- based 90Y- mediated brachytherapy

Background and aims Intimal hyperplasia refers to proliferation and migration of vascular smooth muscle cells primarily in the tunica intima, resulting in arterial wall thickening and decreased arterial lumen size. Neointimal hyperplasia is the major cause of restenosis after percutaneous carotid interventions such as stenting or angioplasty. The aim of this study was to investigate the effect of combined shock wave enhanced sonoporation therapy and catheter-based 90Y-mediated β-brachytherapy on neointimal hyperplasia regression in an animal model, wherein diagnostic B-mode ultrasound is combined with therapy system, with a goal of increased safety. Methods Endothelial balloon catheter denudation of the abdominal aorta of golden Syrian hamsters was performed. Histopathologic evaluation confirmed neointimal hyperplasia formation in all of the hamsters' arteries. The treatment group underwent intravenous lipid-based encapsulated paclitaxel nanoparticles (10mg/kg)-mediated extracorporeal confocal dual pulse low-level focused electrohydraulic shock wave (V=15 kV, F=2 Hz, Impulses = 50 and V=10 kV, F=0.2 Hz, Impulses = 150) enhanced sonoporation therapy accompanied by catheter-based 90Y-mediated β-brachytherapy (90Y, 15 Gy), guided by simultaneous B-mode ultrasound imaging. Results B-mode ultrasound guided combined shock wave enhanced sonoporation therapy and β-brachytherapy was feasible and appeared safe for the targeting of stenosis in the aorta artery. Furthermore, pathological results showed a significant reduction in the mean value for smooth muscle hyperplasia cells density, lumen wall thickness and percentage of luminal cross- sectional area of stenosis in the treatment group compared with the other groups (p<0.05). Conclusions Enhanced toxicity effect of paclitaxel, induced by enhanced sonoporation effect of shock wave therapy, due to inertial cavitation effect of collapsed capsules and dual pulse system application accompanied by apoptotic effect of brachytherapy, can cause to neointimal hyperplasia regression. Combined shock wave enhanced sonoporation therapy and β-brachytherapy is significantly associated with reduced aorta artery stenosis in hamsters. The mechanism may relate to reduced smooth muscle hyperplasia cells and inflammation in the tunica intima. FUNDunding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): Mehrad Research Lab

B- mode ultrasound- guided balloon angioplasty of occluded artery accompanied by combined focused ultrasound sonodynamic therapy and catheter- based 192Ir- mediated brachytherapy

Background and aims Three mechanisms are responsible for the development of restenosis: elastic recoil, intimal hyperplasia and late vascular constriction, all grouped under the catch phrase “negative remodeling”. Neointimal hyperplasia is usually defined in an artery as thickening of the intimal layer after an injury such as balloon angioplasty methods. The aim of this study was to evaluate the effect of combined ultrasound sonodynamic therapy and catheter- based 192Ir-mediated β-brachytherapy on restenosis reduction after balloon angioplasty. Methods Briefly, golden Syrian hamsters were submitted to common carotid artery advanced atherosclerotic occlusion by primary perivascular Co2 laser-mediated far-infrared injury followed by a 2% cholesterol-rich diet for six weeks. Histopathology results showed the formation of a thick-cap fibroatheromatic plaque, resulted to occlusion in all of the hamsters' arteries. Then treatment group (n=10) underwent B-mode ultrasound-guided balloon angioplasty followed by combined pulsed low level focused ultrasound (F=750 KHz, I=1.5 W/cm2, PD=120 ms)-mediated sonosensitizer protoporphyrin-IX-loaded PESDA (Perfluorocarbon Exposed Sonicated Dextrose Albumin) microbubbles (100ml/kg, 2–5×105 bubbles/ml) sonodynamic therapy and catheter- based β-brachytherapy (125I−, 18 Gy). Results Results from ultrasonography and histopathology showed a significant reduction in the mean value for macrophages and smooth muscle hyperplasia cells density after balloon angioplasty in the treated group compared with the other groups (p<0.05). Conclusions Enhanced anti-inflammatory effect of sonodynamic therapy, induced by collapsed microbubbles accompanied by apoptotic effect of β-brachytherapy, can cause to reduce the inflammation and smooth muscle hyperplasia cells in the intimal layer. FUNDunding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): Mehrad Research Lab