A Systematic Comparison of 18F-C-SNAT to Established Radiotracer Imaging Agents for the Detection of Tumor Response to Treatment

Abstract

Purpose An early readout of tumor response to therapy through measurement of drug or radiation-induced cell death may provide important prognostic indications and improved patient management. It has been shown that the uptake of 18F-C-SNAT can be used to detect early response to therapy in tumors by positron emission tomography via a mechanism of caspase 3-triggered nanoaggregation. Experimental Design Here, we compared the preclinical utility of 18F-C-SNAT for the detection of drug-induced cell death to clinically evaluated radiotracers, 18F-FDG, 99mTc-Annexin V and 18F-ML-10 in tumor cells in culture, and in tumor-bearing mice in vivo. Results In drug-treated lymphoma cells, 18F-FDG, 99mTc-Annexin V and 18F-C-SNAT cell-associated radioactivity correlated well to levels of cell death (R2 > 0.8; P < 0.001), with no correlation measured for 18F-ML-10 (R2 = 0.05; P > 0.05). A similar pattern of response was observed in two human NSCLC cell lines following carboplatin treatment. EL-4 tumor uptake of 99mTc-Annexin V and 18F-C-SNAT were increased 1.4- and 2.1-fold, respectively in drug-treated versus naïve control animals (P < 0.05), although 99mTc-Annexin V binding did not correlate to ex vivo TUNEL staining of tissue sections. A differential response was not observed with either 18F-FDG or 18F-ML-10. Conclusions We have demonstrated here that 18F-C-SNAT can sensitively detect drug-induced cell death in murine lymphoma and human NSCLC. Despite favorable image contrast obtained with 18F-C-SNAT, the development of next generation derivatives, using the same novel and promising uptake mechanism, but displaying improved biodistribution profiles, are warranted for maximum clinical utility.

Early Prediction of Tumor Response to Treatment: Preclinical Validation of 99mTc-Duramycin

“…The increase in 99m Tc-duramycin accumulation in treated tumors versus the vehicle group was in the range of other cell death-imaging radiotracers (1.5-to 2.8-fold). For example, in a systematic study comparing different apoptosis imaging agents, Whitney et al found a 1.4-to 2.1-fold increase in 99m Tc-annexin V and 18 F-C-SNAT uptake in lymphoma tumors of mice treated with etoposide (13). In our study, the increase in 99m Tc-duramycin uptake was restricted to the tumors; there was no relevant background uptake in nontargeted organs (11).…”

Avenues to molecular imaging of dying cells: Focus on cancer

“…255 An elegant solution to the problem of intracellular retention of the cleaved substrate has recently been provided by the so-called "smart probes" which display intramolecular macrocyclization and in situ nanoaggregation upon activation by caspase-3. [256][257][258] Due to sequence homology among the caspases, most caspase probes are not specific for caspase-3 or caspase-7. However, recent research on activity-based probes has shown that the selectivity of such probes for a single caspase can be greatly improved by introducing several unnatural amino acids in the peptide recognition sequence.…”

Protease-Sensitive Nanomaterials for Cancer Therapeutics and Imaging

“…107 Additionally, a 18 F-based PET probe was developed which also had significantly higher tumor signal and tumor-to-muscle ratios in murine models in response to tumor therapy. 108,109 The group also applied this technology for apoptosis imaging with caspase-activity in arthritis, 110 highlighting the vast applicability of this probe design to imaging drug efficacy for many diseases.…”