Competitive blocking of salivary gland [

backgroundPSMA-targeted radionuclide therapy (TRT) is a promising treatment for prostate cancer (PCa), but dose-limiting xerostomia can severely limit its clinical adaptation, especially when using alpha-emitting radionuclides. With [

methodsA dose-finding cohort using athymic nude mice demonstrated proof of principle that SG uptake can be selectively blocked by DCFPyL administered either locally via cannulation (CAN group) or systemically (SYS group). The experiments were repeated in a validation cohort of 22RV1 tumor-bearing mice. Submandibular glands (SMG) of CAN mice were locally blocked with either saline or DCFPyL (dose range: 0.01× to 1000× molar equivalent of the radioactive [18F]DCFPyL dose). The radioactive dose of [18F]DCFPyL was administered systemically 10 min later and the mice euthanized after 1 h for biodistribution studies. Toxicity studies were done at up to 1000× dose.

resultsIn the dose-finding cohort, the SYS group showed a dose-dependent 12-40% decrease in both the SMG T/B and the kidney (tumor surrogate). Mild blocking was observed at 0.01× , with maximal blocking reached at 1× with no additional blocking up to 1000× . In the CAN group, blocking at the 0.1× and 1× dose levels resulted in a similar 42-53% decrease, but without the corresponding decrease in kidney uptake as seen in the SYS group. Some evidence of "leakage" of DCFPyL from the salivary gland into the systemic circulation was observed. However, experiments in 22RV1 tumor-bearing mice at the 0.1× and 1× dose levels confirm that, at the appropriate blocking dose, SG uptake of [18F]DCFPyL can be selectively reduced without affecting tumor uptake and with no toxicity.

conclusionOur results suggest that direct retrograde instillation of DCFPyL into the SG could predictably and selectively decrease salivary uptake of systemically administered [