Optoacoustic Detection of Early Therapy-Induced Tumor Cell Death Using a Targeted Imaging Agent

Abstract

The development of new treatments and their deployment in the clinic may be assisted by imaging methods that allow an early assessment of treatment response in individual patients. The C2A domain of Synaptotagmin-I (C2Am), which binds to the phosphatidylserine (PS) exposed by apoptotic and necrotic cells, has been developed as an imaging probe for detecting cell death. Multispectral optoacoustic tomography (MSOT) is a real-time and clinically applicable imaging modality that was used here with a near infrared (NIR) fluorophore-labeled C2Am to image tumor cell death in mice treated with a TNF-related apoptosis-inducing ligand receptor 2 (TRAILR2) agonist and with 5-fluorouracil (5-FU). C2Am was labeled with a NIR fluorophore and injected intravenously into mice bearing human colorectal TRAIL-sensitive Colo205 and TRAIL-resistant HT-29 xenografts that had been treated with a potent agonist of TRAILR2 and in Colo205 tumors treated with 5-FU. Three-dimensional (3D) MSOT images of probe distribution showed development of tumor contrast within 3 hours of probe administration and a signal-to-background ratio in regions containing dead cells of >10 after 24 hours. A site-directed mutant of C2Am that is inactive in PS binding showed negligible binding. Tumor retention of the active probe was strongly correlated ( = 0.97, value< 0.01) with a marker of apoptotic cell death measured in histologic sections obtained post mortem. The rapid development of relatively high levels of contrast suggests that NIR fluorophore-labeled C2Am could be a useful optoacoustic imaging probe for detecting early therapy-induced tumor cell death in the clinic. .

Integrin-targeted quantitative optoacoustic imaging with MRI correlation for monitoring a BRAF/MEK inhibitor combination therapy in a murine model of human melanoma

“…Several groups investigated the potential of preclinical optoacoustic imaging with targeted probes for the non-invasive characterization of the tumor microenvironment in vivo [ 16 , 22 – 25 ]. α v ß 3 -integrin-targeted fluorescent probes were studied to qualitatively visualize experimental human breast carcinomas and glioblastomas [ 16 , 24 ].…”

Hand-held optoacoustic imaging: A review

“…Multispectral or spectroscopic OAI can be used with all of the aforementioned OAI methods. For instance, spectroscopic OACT, often termed multispectral optoacoustic tomography (MSOT), has found much success in applications such as visualizing oxygen saturation in the vasculature around tumors, imaging tumors in breast tissue, visualizing sentinel lymph nodes (SLNs), and visualizing vasculature deep in tissues, among others [ [30] , [31] , [32] , [33] , [34] , [35] , [36] , [37] , [38] , [39] ]. Additionally, spectroscopic OMe, often termed multispectral optoacoustic mesoscopy (MSOM), has been used for selectively imaging melanin and blood, as well as visualizing the structure of skin in patients with psoriasis [ 18 , 40 ].…”

Optical and photoacoustic radiofrequency spectroscopic analysis for detecting red blood cell death

“…The aforementioned morphological and functional RBCs changes observed during cancer treatments suggest that photoacoustic (PA) imaging can be used as a non‐invasive tool for monitoring treatment efficacy . The high contrast due to the strong optical absorption of hemoglobin compared to the surrounding tissues at the near infrared window allows PA imaging to extract information about the state of RBCs at depths up to several centimeters .…”

“…QUS parameters have been correlated to the size, concentration and spatial distribution of the non‐resolvable scatterers (i.e. those smaller than the system imaging resolution) . Transducer independent measurements are made by normalizing the frequency spectra to a reference phantom .…”