Optimizing the profile of [99mTc]Tc–Nt(7–13) tracers in pancreatic cancer models by means of protease inhibitors

Abstract

Background: The overexpression of neurotensin subtype 1 receptors (NTS1Rs) in human tumors may be elegantly exploited for directing neurotensin (NT)-based radionuclide carriers specifically to cancer sites for theranostic purposes. We have recently shown that [99mTc]Tc–DT1 ([99mTc]Tc–[N4–Gly7]NT(7–13)) and [99mTc]Tc–DT5 ([99mTc]Tc–[N4–βAla7,Dab9]NT(7–13)) show notably improved uptake in human colon adenocarcinoma WiDr xenografts in mice treated with neprilysin (NEP) inhibitors and/or angiotensin-converting enzyme (ACE) inhibitors compared with untreated controls. Aiming toward translation of this promising approach in NTS1R-positive pancreatic ductal adenocarcinoma (PDAC) patients, we now report on the impact of registered NEP/ACE inhibitors on the performance of [99mTc]Tc–DT1 and [99mTc]Tc–DT5 in pancreatic cancer models. Methods: The cellular uptake of [99mTc]Tc–DT1 and [99mTc]Tc–DT5 was tested in a panel of pancreatic cell lines, and their stability was assessed in mice treated or not treated with Entresto, lisinopril, or their combinations. Biodistribution was conducted in severe combined immunodeficiency (SCID) mice bearing pancreatic AsPC-1 xenografts. Results: The Entresto + lisinopril combination maximized the metabolic stability of the fast-internalizing [99mTc]Tc–DT1 in mice, resulting in notably enhanced tumor uptake (7.05 ± 0.80% injected activity (IA)/g vs. 1.25 ± 0.80% IA/g in non-treated controls at 4 h post-injection; p < 0.0001). Conclusions: This study has shown the feasibility of optimizing the uptake of [99mTc]Tc–DT1 in pancreatic cancer models with the aid of clinically established NEP/ACE inhibitors, in favor of clinical translation prospects.