RESUMO
Quantitative ultrasound (QUS) is a non-invasive imaging modality that permits the detection of tumor response following various cancer therapies. Based on ultrasound signal scattering from the biological system, scatterer size, and concentration of microscopic scatterers, QUS enables the rapid characterization of tumor cell death. In this study, tumor response to ultrasound-stimulated microbubbles (USMB) and hyperthermia (HT) in tumor-bearing mice, with prostate cancer xenografts (PC3), was examined using QUS. Treatment conditions included 1% (v/v) Definity microbubbles stimulated at ultrasound pressures (0, 246, and 570 kPa) and HT treatment (0, 10, 40, and 50 minutes). Three ultrasound backscatter parameters, mid-band fit (MBF), 0-MHz spectral intercept (SI), and spectral slope (SS) were estimated prior to, and 24 hours after treatment. Additionally, histological assessment of tumor cell death and tissue microstructural changes was used to complement the results obtained from ultrasound data. Results demonstrated a significant increase in QUS parameters (MBF and SI) followed combined USMB and HT treatment (P<0.05). In contrast, the backscatter parameters from the control (untreated) group, and USMB only group showed minimal changes (P>0.05). Furthermore, histological data demonstrated increased cell death and prominent changes in cellular and tissue structure, nucleus size, and subcellular constituent orientation followed combined treatments. The findings suggested that QUS parameters derived from the ultrasound backscattered power spectrum may be used to detect HT treatment effects in prostate cancer tumors in vivo.
RESUMO
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.
