Optimizing the Profile of [99mTc]Tc-NT(7-13) Tracers in Pancreatic Cancer Models by Means of Protease Inhibitors.
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.
['Kanellopoulos|Panagiotis|P|', 'Nock|Berthold A|BA|0000-0002-6028-9112', 'Krenning|Eric P|EP|', 'Maina|Theodosia|T|0000-0002-1123-2486']
D000613:Aminobutyrates D000818:Animals D001713:Biphenyl Compounds D021441:Carcinoma, Pancreatic Ductal D045744:Cell Line, Tumor D004338:Drug Combinations D004355:Drug Stability D006801:Humans D017706:Lisinopril D008297:Male D051379:Mice D016513:Mice, SCID D009368:Neoplasm Transplantation D009496:Neurotensin D015609:Organotechnetium Compounds D010190:Pancreatic Neoplasms D010455:Peptides D011480:Protease Inhibitors D018028:Receptors, Neurotensin D013777:Tetrazoles D014018:Tissue Distribution D000068756:Valsartan
pancreatic cancer neurotensin neurotensin subtype 1 receptor theranostics neprilysin Entresto lisinopril clinical translation [99mTc]Tc radiotracer angiotensin_converting enzyme