Non-invasive Monitoring of Ultrasound-Stimulated Microbubble Radiation Enhancement Using Photoacoustic Imaging

Abstract

Modulation of the tumour microvasculature has been demonstrated to affect the effectiveness of radiation, stimulating the search for anti-angiogenic and vascular-disrupting treatment modalities. Microbubbles stimulated by ultrasound have recently been demonstrated as a radiation enhancer when used with different cancer models including PC3. Here, photoacoustics imaging technique was used to assess this treatment’s effects on haemoglobin levels and oxygen saturation. Correlations between this modality and power doppler assessments of blood flow, and histology measurements of vascular integrity and cell death were also investigated. Xenograft prostate tumours in SCID mice were treated with 0, 2, or 8 Gy radiation combined with microbubbles exposed to 500 kHz ultrasound at a peak negative pressure of 0, 570, and 750 kPa. Tumours were assessed and levels of total haemoglobin, oxygen saturation were measured using photoacoustics before and 24 hours after treatment along with power doppler measured blood flow. Mice were then sacrificed and tumours were assessed for cell death and vascular composition using immunohistochemistry. Treatments using 8 Gy and microbubbles resulted in oxygen saturation decreasing by 28 ± 10% at 570 kPa and 25 ± 29% at 750 kPa, which corresponded to 44 ± 9% and 40 ± 14% respective decreases in blood flow as measured with power doppler. Corresponding histology indicated 31 ± 5% at 570 kPa and 37 ± 5% at 750 kPa in terms of cell death. There were drops in intact vasculature of 15 ± 2% and 20 ± 2%, for treatments at 570 kPa and 750 kPa. In summary, photoacoustic measures of total haemoglobin and oxygen saturation paralleled changes in power doppler indicators of blood flow. Destruction of tumour microvasculature with microbubble-enhanced radiation also led to decreases in blood flow and was associated with increases in cell death and decreases in intact vasculature as detected with CD31 labeling.

Ultrasound-stimulated microbubble enhancement of radiation response

“…Corresponding immunohistochemistry indicated 1±2% at 570 kPa (p±0.033) and 20±2% at 750 kPa (p±0.015) decreases in intact tumour vasculature, and 31±5% at 570 kPa (p = 0.005) and 37±5% at 750 kPa (Briggs et al, 2014) (Figure 5).…”

“…For treatments with prostate tumours, photoacoustic data was assessed quantitatively and indicated significant decreases in oxygen saturation across all treatment conditions where radiation alone or ultrasound-stimulated microbubbles, or the combination of these were administered (p < 0.05) (Briggs et al, 2014). Specifically, treatments using 8 Gy and microbubbles resulted in oxygen saturation decreases of 28±10% at 570 kPa and with 750 kPa a decrease of 25±29%, which corresponded to 44±9% and 40±14% respective decreases in blood flow as measured with power Doppler ultrasound.…”

Photoacoustic simulation of microvessel bleeding: spectral analysis and its implication for monitoring vascular-targeted treatments

“…Photoacoustic (PA) imaging has been proposed to monitor tumour response to various types of cancer therapies [1], [2]. A common response to these therapies can involve bleeding of tumour microvessels.…”

Ultrasound-stimulated microbubble enhancement of radiation treatments: endothelial cell function and mechanism

“…Current reports indicate a significant sensitization of tumour cells when radiation is combined with ultrasound-stimulated microbubble exposure [ 3 , 4 , 5 , 6 , 7 ]. In vitro experiments using endothelial cells have also confirmed an enhancement of radiation effect [ 8 ] and activation of ceramide-related cell death, supporting the idea that these vascular cells are the primary target in this therapy.…”