Pharmacokinetic analysis of targeted nanonubbles for quantitative assessment of PSMA expression in prostate cancer

Despite showing promise, the sensitivity of contrast enhanced ultrasound (CEUS) for prostate cancer diagnosis is still limited. The introduction of novel microbubbles (MBs) targeted to the vascualar endhotelial growth receptor factor 2 has opened new possibilites for molecular imaging of prostate cancer. However, the detection rate in a phase-0 clinical trial was still limited to 65%. More effective contrast agents are needed to improve diagnostic accuracy. Recently, ultrasound nanobubbles (NBs) are emerging as promising agents for improved cancer diagnostics and therapy. Thanks to their reduced diameter, which is about 10 times smaller than MBs, they can cross the vascular endhotelium, providing greater possibilities for targeted imaging and therapy, including targets no longer limited to the vessel wall. In this context, a long-circulating NB targeted to the prostate-specific membrane antigent (PSMA) was recently developed, showing promise for selective accumulation in tumors expressing PSMA. In this work, we propose pharmacokinetic modeling of the kinetics of PSMA-targeted NBs by the simplified reference tissue model. While this model has been originially developed for receptor kinetic studies in nuclear medicine, it is here adapted for CEUS, enabling quantitative assessment of PSMA expression by estimation of the binding potential BP. The model is validated by comparing the estimated binding parameter obtained for three different US contrast agents (conventional MBs, non-targeted NBs, and PSMA-targeted NBs) in a dual tumor mouse model, carrying a PSMA-positive tumor in one flank, and a PSMA-negative tumor in the other flank.