Noninvasive Anatomical and Functional Imaging of Orthotopic Glioblastoma Development and Therapy using Multispectral Optoacoustic Tomography

Abstract

PURPOSE: Here we demonstrate the potential of multispectral optoacoustic tomography (MSOT), a new non-invasive structural and functional imaging modality, to track the growth and changes in blood oxygen saturation (sO2) in orthotopic glioblastoma (GBMs) and the surrounding brain tissues upon administration of a vascular disruptive agent (VDA). METHODS: Nude mice injected with U87MG tumor cells were longitudinally monitored for the development of orthotopic GBMs up to 15 days and observed for changes in sO2 upon administration of combretastatin A4 phosphate (CA4P, 30 mg/kg), an FDA approved VDA for treating solid tumors. We employed a newly-developed non-negative constrained approach for combined MSOT image reconstruction and unmixing in order to quantitatively map sO2 in whole mouse brains. RESULTS: Upon longitudinal monitoring, tumors could be detected in mouse brains using single-wavelength data as early as 6 days post tumor cell inoculation. Fifteen days post-inoculation, tumors had higher sO2 of 63 ± 11% (n = 5, P < .05) against 48 ± 7% in the corresponding contralateral brain, indicating their hyperoxic status. In a different set of animals, 42 days post-inoculation, tumors had lower sO2 of 42 ± 5% against 49 ± 4% (n = 3, P < .05) in the contralateral side, indicating their hypoxic status. Upon CA4P administration, sO2 in 15 days post-inoculation tumors dropped from 61 ± 9% to 36 ± 1% (n = 4, P < .01) within one hour, then reverted to pre CA4P treatment values (63 ± 6%) and remained constant until the last observation time point of 6 hours. CONCLUSION: With the help of advanced post processing algorithms, MSOT was capable of monitoring the tumor growth and assessing hemodynamic changes upon administration of VDAs in orthotopic GBMs.

Non-Invasive Evaluation of Acute Effects of Tubulin Binding Agents: A Review of Imaging Vascular Disruption in Tumors

“…This is also available on the iThera Acuity system, which is designed for larger animals and human investigations. Several studies have reported dynamic vascular response of tumors in mice or rats to vascular disruption caused by CA4P, CA1P and EPC2407 [ 92 , 118 , 119 , 130 , 239 , 240 ]. In most cases, changes in [HbO 2 ] and [Hb] are examined, thereby also revealing vascular oxygen saturation (sO 2 ).…”

Photoacoustic Neuroimaging - Perspectives on a Maturing Imaging Technique and its Applications in Neuroscience

“…Volumetric imaging of glioblastoma in nude mice was demonstrated without contrast agents by exploiting differential contrast under illumination with 800 and 850 nm. The authors also quantified tumor O 2 saturation, which increased 15 days after inoculation, whereas the tissue became hypoxic 42 days after inoculation (Balasundaram et al, 2018). In another study, integrin expressing tumor cells were tagged with an IRDye800-based contrast agent while also assessing tumor SO 2 , which was 13% lower than in healthy brain tissue (Li M. et al, 2008).…”

Non-Invasive Evaluation of Acute Effects of Tubulin Binding Agents: A Review of Imaging Vascular Disruption in Tumors

“…This is also available on the iThera Acuity system, which is designed for larger animals and human investigations. Several studies have reported dynamic vascular response of tumors in mice or rats to vascular disruption caused by CA4P, CA1P and EPC2407 [92,117,118,129,229,230]. In most cases, changes in [HbO2] and [Hb] are examined, thereby also revealing vascular oxygen saturation (sO2).…”