Ultrasound microbubble potentiated enhancement of hyperthermia-effect in tumours

Autoři: Deepa Sharma aff001;  Anoja Giles aff001;  Amr Hashim aff001;  Jodi Yip aff001;  Yipeng Ji aff001;  Natalie Ngoc Anh Do aff001;  Juliana Sebastiani aff001;  William Tyler Tran aff001;  Golnaz Farhat aff001;  Michael Oelze aff005;  Gregory J. Czarnota aff001
Působiště autorů: Physical Sciences, Sunnybrook Research Institute, Toronto, ON, Canada aff001;  Department of Radiation Oncology, Sunnybrook Health Sciences Centre, Toronto, ON, Canada aff002;  Department of Radiation Oncology, University of Toronto, Toronto, ON, Canada aff003;  Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada aff004;  Department of Electrical and Computer Engineering, University of Illinois, Urbana-Champaign, IL, United States of America aff005
Vyšlo v časopise: PLoS ONE 14(12)
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.pone.0226475


It is now well established that for tumour growth and survival, tumour vasculature is an important element. Studies have demonstrated that ultrasound-stimulated microbubble (USMB) treatment causes extensive endothelial cell death leading to tumour vascular disruption. The subsequent rapid vascular collapse translates to overall increases in tumour response to various therapies. In this study, we explored USMB involvement in the enhancement of hyperthermia (HT) treatment effects. Human prostate tumour (PC3) xenografts were grown in mice and were treated with USMB, HT, or with a combination of the two treatments. Treatment parameters consisted of ultrasound pressures of 0 to 740 kPa, the use of perfluorocarbon-filled microbubbles administered intravenously, and an HT temperature of 43°C delivered for various times (0–50 minutes). Single and multiple repeated treatments were evaluated. Tumour response was monitored 24 hours after treatments and tumour growth was monitored for up to over 30 days for a single treatment and 4 weeks for multiple treatments. Tumours exposed to USMB combined with HT exhibited enhanced cell death (p<0.05) and decreased vasculature (p<0.05) compared to untreated tumours or those treated with either USMB alone or HT alone within 24 hours. Deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) staining and cluster of differentiation 31 (CD31) staining were used to assess cell death and vascular content, respectively. Further, tumours receiving a single combined USMB and HT treatment exhibited decreased tumour volumes (p<0.05) compared to those receiving either treatment alone when monitored over the duration of 30 days. Additionally, tumour response monitored weekly up to 4 weeks demonstrated a reduced vascular index and tumour volume, increased fibrosis and lesser number of proliferating cells with combined treatment of USMB and HT. Thus in this study, we characterize a novel therapeutic approach that combines USMB with HT to enhance treatment responses in a prostate cancer xenograft model in vivo.

Klíčová slova:

Apoptosis – Cancer treatment – Cell death – Cell staining – Collagens – Fibrosis – Hyperthermia – Radiation therapy


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