Monitoring Tumor Response to Vascular Disrupting Agent Using Photoacoustic Tomography and Multiparametric MRI

1408 Objectives Photoacoustic imaging is a non-ionizing imaging technique that has recently attracted great attention due to its hybrid way of generating in vivo images. It takes advantage of both the high sensitivity of optical imaging and high spatial resolution and penetration depth of ultrasound to provide in vivo images at high temporal and spatial resolution. In particular, the well characterized endogenous absorption spectra of oxy- and deoxyhemoglobin can be utilized to determine the composition of oxy- and deoxyhemoglobin in blood-filled vasculature using a linear regression technique for multispectral unmixing of photoacoustic data. Vascular disrupting agents (VDAs) selectively shutdown the tumor vasculature, and, therefore, induce tumor hypoxia. In this study, we used photoacoustic imaging to assess the dynamic changes of oxy- and deoxyhemoglobin following the administration of OXi6197, a newly developed dihydronaphthalene-based VDA inspired by combretastatin A-4 phosphate (CA4P) and colchicine, in a subcutaneous lung cancer rat model. Methods A549 human lung cancer cells were implanted subcutaneously in the thigh of nude rats. MRI and photoacoustic imaging were performed before and after the administration of VDA (MRI was performed one day later and photoacoustic imaging was performed two days later). Photoacoustic imaging was performed using an iThera MSOT 256 system. The anesthetized rats breathed air (21%O2) for 5 minutes followed by 100% oxygen for 8 minutes. Five wavelengths (715, 730, 760, 800 and 850 nm) were selected to assess oxy- and deoxyhemoglobin concentrations. Reconstruction was performed using a back-projection algorithm. Multispectral analysis was performed using linear regression with the MSOT software. MRI was performed at 4.7 T including interleaved BOLD (blood oxygen level dependent R2[asterisk]: multi-echo gradient echo) and TOLD (tissue oxygen level dependent T1w: gradient echo) with respect to an oxygen challenge (from air to 100% O2). DCE-MRI (dynamic contrast enhanced) was performed with IV injection of gadolinium contrast (Gadavist; 0.1 mmol/kg). Results At baseline, the tumor showed a decrease in deoxyhemoglobin and increase of oxyhemoglobin upon oxygen breathing. Post administration of VDA, photoacoustic imaging showed lack of response to oxygen breathing for both oxy- and deoxyhemoglobin (Fig. A-F). Oxygen-sensitive MRI showed progression of hypoxia 24 hours after administration of VDA. The observation is consistent with a decrease in perfusion after VDA administration, revealed by maximum intensity projection (MIP) images, area under the curve (AUC; Figure G and H) and slope. Following VDA maximum signal enhancement was delayed significantly especially for the central tumor regions. Figure: Photoacoustic imaging showed increase of oxyhemoglobin from air (A) to oxygen breathing (B) at baseline (tumor outlined in A and C). Only minimal responses to oxygen were observed two days after the administration of VDA (C: air breathing; D: oxygen breathing). Comparison of normalized deoxy- (E) and oxyhemoglobin (F) at both time points. A significant decrease in AUC from DCE MRI was observed confirming reduction of perfusion (G: before treatment; H: one day post VDA). Conclusions Both photoacoustic imaging and multiparametric MRI revealed heterogonous perfusion in the tumor. A decrease of perfusion was evident in response to OXi6197. $$graphic_83DF1A2C-C5F9-4E00-B051-27215DAC3865$$