TY - JOUR
T1 - Reshaping [99mTc]Tc-DT11 to DT14D Tagged with Trivalent Radiometals for NTS1R-Positive Cancer Theranostics
AU - Kanellopoulos, Panagiotis
AU - Nock, Berthold A.
AU - Krenning, Eric P.
AU - Maina, Theodosia
N1 - Publisher Copyright:
© 2025 by the authors.
PY - 2025/2/28
Y1 - 2025/2/28
N2 - Background/Objectives: Radiotheranostics of neurotensin subtype 1 receptor (NTS1R)-expressing tumors, like pancreatic, gastrointestinal, or prostate cancer, has attracted considerable attention in recent years. Still, the fast degradation of neurotensin (NT)-based radioligands, by angiotensin-converting enzyme (ACE), neprilysin (NEP), and other proteases, has considerably compromised their efficacy. The recently introduced [99mTc]Tc-DT11 (DT11, N4-Lys(MPBA-PEG4)-Arg-Arg-Pro-Tyr-Ile-Leu-OH; N4, 6-(carboxy)-1,4,8,11-tetraazaundecane) has displayed promising uptake in NTS1R-positive tumors in mice and enhanced resistance to both ACE and NEP by virtue of the lateral MPBA-PEG4 (MPBA, 4-(4-methylphenyl)butyric acid; PEG4, 14-amino-3,6,9,12-tetraoxatetradecan-1-oic acid) chain attached to the ε-NH2 of Lys7. We were next interested in investigating whether these qualities could be retained in DT14D, likewise modified at Lys7 but carrying the universal chelator DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) via a (βAla)3 spacer at the α-NH2 of Lys7. This chelator switch enables the labeling of DT14D with a wide range of trivalent radiometals suitable for true theranostic applications, not restricted to the diagnostic imaging of NTS1R-positive lesions only by single-photon emission computed tomography (SPECT). Methods: DT14D was labeled with Ga-67 (a surrogate for the positron emission tomography radionuclide Ga-68), In-111 (for SPECT), and Lu-177 (applied in radiotherapy). The resulting radioligands were tested in NTS1R-expressing pancreatic cancer AsPC-1 cells and mice models. Results:[67Ga]Ga/[111In]In/[177Lu]Lu-DT14D displayed high affinity for human NTS1R and internalization in AsPC-1 cells. They remained >70% intact 5 min after entering the mice’s circulation, displaying NTS1R-specific uptake in AsPC-1 xenografts. Conclusions: Suitably side-chain modified NT analogs show enhanced metabolic stability and hence better prospects for radiotheranostic application in NTS1R-positive cancer.
AB - Background/Objectives: Radiotheranostics of neurotensin subtype 1 receptor (NTS1R)-expressing tumors, like pancreatic, gastrointestinal, or prostate cancer, has attracted considerable attention in recent years. Still, the fast degradation of neurotensin (NT)-based radioligands, by angiotensin-converting enzyme (ACE), neprilysin (NEP), and other proteases, has considerably compromised their efficacy. The recently introduced [99mTc]Tc-DT11 (DT11, N4-Lys(MPBA-PEG4)-Arg-Arg-Pro-Tyr-Ile-Leu-OH; N4, 6-(carboxy)-1,4,8,11-tetraazaundecane) has displayed promising uptake in NTS1R-positive tumors in mice and enhanced resistance to both ACE and NEP by virtue of the lateral MPBA-PEG4 (MPBA, 4-(4-methylphenyl)butyric acid; PEG4, 14-amino-3,6,9,12-tetraoxatetradecan-1-oic acid) chain attached to the ε-NH2 of Lys7. We were next interested in investigating whether these qualities could be retained in DT14D, likewise modified at Lys7 but carrying the universal chelator DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) via a (βAla)3 spacer at the α-NH2 of Lys7. This chelator switch enables the labeling of DT14D with a wide range of trivalent radiometals suitable for true theranostic applications, not restricted to the diagnostic imaging of NTS1R-positive lesions only by single-photon emission computed tomography (SPECT). Methods: DT14D was labeled with Ga-67 (a surrogate for the positron emission tomography radionuclide Ga-68), In-111 (for SPECT), and Lu-177 (applied in radiotherapy). The resulting radioligands were tested in NTS1R-expressing pancreatic cancer AsPC-1 cells and mice models. Results:[67Ga]Ga/[111In]In/[177Lu]Lu-DT14D displayed high affinity for human NTS1R and internalization in AsPC-1 cells. They remained >70% intact 5 min after entering the mice’s circulation, displaying NTS1R-specific uptake in AsPC-1 xenografts. Conclusions: Suitably side-chain modified NT analogs show enhanced metabolic stability and hence better prospects for radiotheranostic application in NTS1R-positive cancer.
UR - https://www.scopus.com/pages/publications/105001138245
U2 - 10.3390/pharmaceutics17030310
DO - 10.3390/pharmaceutics17030310
M3 - Article
C2 - 40142972
AN - SCOPUS:105001138245
SN - 1999-4923
VL - 17
JO - Pharmaceutics
JF - Pharmaceutics
IS - 3
M1 - 310
ER -
