Abstract
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Objectives To obtain quantitative in vivo pharmacokinetic measurements of the apoptosis / caspase-3 activated nano-aggregation tracer 18F-C-SNAT in a clinically relevant mouse model of tumor therapy.
Methods HeLa tumor xenografts were implanted on the shoulder of nude mice, and were allowed to grow to a minimum of 5x5 mm before treatment with a series of chemotherapeutic drug injection. All mice (control n=6, treated n=5) were anesthetized with isoflurane and placed in a microPET/CT. A 15-min CT scan was performed followed by injection of 18F-C-SNAT (184 ± 54 µCi) and a 120-min dynamic PET scan. Tracer uptake over time was measured in regions of interest in the PET image by using the CT as an anatomical guide. The whole tumor region was subjected to a threshold algorithm selecting the top25% intensity pixels, generating a second region associated with the treatment response. Tracer pharmacokinetics was calculated using a 2-tissue compartmental model while using the tracer concentration in the left ventricle as an estimated input function.
Results Uptake of 18F-C-SNAT was found to be 2.3 times higher in the treated tumors over the whole scan when comparing the area under curve — maximum uptake of 6.1 (± 1.1 sem) %ID/g in treated tumors compared with 2.5 (± 0.4 sem) %ID/g in controls — and 2.5 times higher tumor/muscle ratio in treated tumors (9.0 ± 1.7 sem) compared with controls (3.6 ± 0.6 sem) at the end of scan. The pharmacokinetics of 18F-C-SNAT in treated mice was found to be different from controls, the flow in and out (K1 and k2) of the treated tumor was higher but the net delivery (K1/k2) similar, the accumulation rate of 18F-C-SNAT (k3) was 1.85 times higher — whereas the washout rate (k4) was similar.
Conclusions 18F-C-SNAT show significant increases in uptake, tumor/muscle ratios and accumulation rate in a clinically relevant model of tumor therapy. These findings support our theory that chemotherapeutic induced tumor apoptosis leads to higher accumulation of 18F-C-SNAT and thus enable the use of 18F-C-SNAT as a PET tracer for imaging tumor therapy.
Research Support Mikael Palner is supported with a post doctoral fellowship from the Danish Cancer Society.