Ultrasound-stimulated microbubbles enhanced vascular disruption in fractionated radiotherapy-treated tumours via ASMase activation

Recent studies have indicated that radiotherapy affects tumour vasculature as well as tumour cells. The use of ultrasound-stimulated microbubbles (USMB) can potentially enhance the effects of radiotherapy through the activation of the acid sphingomyelinase (ASMase) - ceramide pathway. ASMase knockout (ASMase -/-) and wild type (WT) mice bearing fibrosarcoma (MCA/129 tumour line) were treated with 10 Gy or 20 Gy in 5 fractions alongside or independently of USMB treatments. Results indicated that tumour responses to fXRT were enhanced when fXRT was coupled with USMB as part of the treatment regimen. Sphingosine-1-Phosphate (S1P) treated and ASMase -/- mice demonstrated radioresistance against fractionated radiotherapy (fXRT) alone while the combination treatment only showed radioresistance in ASMase -/- mice. Results indicated that in WT and S1P cohorts, the use of USMB+fXRT was capable of enhancing tumour response compared to USMB or fXRT alone. While in WT and S1P cohorts there was enhanced vascular disruption, ASMase -/- cohorts demonstrated no significant vascular disruption, indicating the importance of ASMase in facilitating vascular changes in response to fXRT and USMB.