Abstract
We have demonstrated that exposing human breast tumour xenografts to ultrasound-stimulated microbubbles enhances tumour cell death and vascular disruption resulting from hyperthermia treatment. The aim of this study was to investigate the effect of varying the hyperthermia and ultrasound-stimulated microbubbles treatment parameters in order to optimize treatment bioeffects. Human breast cancer (MDA-MB-231) tumour xenografts in severe combined immunodeficiency (SCID) mice were exposed to varying microbubble concentrations (0%, 0.1%, 1% or 3% v/v) and ultrasound sonication durations (0, 1, 3 or 5 min) at 570 kPa peak negative pressure and central frequency of 500 kHz. Five hours later, tumours were immersed in a 43°C water bath for varying hyperthermia treatment durations (0, 10, 20, 30, 40, 50 or 60 minutes). Results indicated a significant increase in tumour cell death reaching 64 ± 5% with combined treatment compared to 11 ± 3% and 26 ± 5% for untreated and USMB-only treated tumours, respectively. A similar but opposite trend was observed in the vascular density of the tumours receiving the combined treatment. Optimal treatment parameters were found to consist of 40 minutes of heat with low power ultrasound treatment microbubble parameters of 1 minute of sonification and a 1% microbubble concentration.
Highlights
Hyperthermia (HT) therapy, defined as the moderate elevation of body tissues to temperatures of 39–45 ̊C, has been used as a compelling treatment of cancers for centuries [1]
ultrasound-stimulated microbubbles (USMB) combined with HT results in increased cell death and vascular disruption in MDA-MB-231 xenografts
Large areas of cell death, determined from coincident transferase dUTP nick-end labeling (TUNEL) and hematoxylin and eosin (H&E) stained sections, were found in all treated tumours compared to controls
Summary
Hyperthermia (HT) therapy, defined as the moderate elevation of body tissues to temperatures of 39–45 ̊C, has been used as a compelling treatment of cancers for centuries [1]. The critical event appears to be protein denaturation and aggregation, which in turn can lead to inhibition of DNA repair, inhibition of de novo DNA synthesis, mitotic catastrophe, cytoskeleton damage, and loss of membrane integrity [5, 9, 10]. Another mechanism influencing cell death is HT-induced antitumour immunity, tumour vascular damage resulting in decreased blood flow, and increased generation of reactive oxygen species [5, 7, 10]. Hyperthermia’s pleiotropic effects and favorable history substantiate its further investigation into clinical use
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