Preclinical kinetic analysis of the caspase-3/7 PET tracer 18F-C-SNAT: Quantifying the changes in blood flow and tumor retention after chemotherapy

Abstract

Early detection of tumor response to therapy is crucial to the timely identification of the most efficacious treatments. We recently developed a novel apoptosis imaging tracer, 18F-C-SNAT (C-SNAT is caspase-sensitive nanoaggregation tracer), that undergoes an intramolecular cyclization reaction after cleavage by caspase-3/7, a biomarker of apoptosis. This caspase-3/7-dependent reaction leads to an enhanced accumulation and retention of 18F activity in apoptotic tumors. This study aimed to fully examine in vivo pharmacokinetics of the tracer through PET imaging and kineticmodeling in a preclinical mousemodel of tumor response to systemic anticancer chemotherapy. Methods: Tumor-bearing nude mice were treated 3 times with intravenous injections of doxorubicin before undergoing a 120-min dynamic 18F-C-SNAT PET/CT scan. Time-activity curves were extracted from the tumor and selected organs. A 2-tissue-compartment model was fitted to the time- activity curves from tumor and muscle, using the left ventricle of the heart as input function, and the pharmacokinetic rate constants were calculated. Results: Both tumor uptake (percentage injected dose per gram) and the tumor-to-muscle activity ratio were significantly higher in the treated mice than untreated mice. Pharmacokinetic rate constants calculated by the 2-tissue-compartment model showed a significant increase in delivery and accumulation of the tracer after the systemic chemotherapeutic treatment. Delivery of 18F-C-SNAT to the tumor tissue, quantified as K1, increased from 0.31 g· (mL·min)-1 in untreated mice to 1.03 g· (mL·min)-1 in treated mice, a measurement closely related to changes in blood flow. Accumulation of 18F-C-SNAT, quantified as k3, increased from 0.03 to 0.12 min-1, proving a higher retention of 18F-C-SNAT in treated tumors independent from changes in blood flow. An increase in delivery was also found in the muscular tissue of treated mice without increasing accumulation. Conclusion: 18F-CSNAT has significantly increased tumor uptake and significantly increased tumor-to-muscle ratio in a preclinical mouse model of tumor therapy. Furthermore, our kinetic modeling of 18F-C-SNAT shows that chemotherapeutic treatment increased accumulation (k3) in the treated tumors, independent of increased delivery (K1).