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Five Stabilized 111In-labeled neurotensin analogs in nude mice bearing HT29 tumors
Paul J J M Janssen1, Moniaue de Visser, Suzanne M Verwijnen
1Hospital Pharmacy, Erasmus MC, Rotterdam, The Netherlands. p.janssen@erasmusmc.nl
Abstract:
Neurotensin (NT) receptors are overexpressed in different human tumors, such as human ductal pancreatic adenocarcinoma. New stable neurotensin analogs with high receptor affinity have been synthesized by replacing arginine residues with lysine and arginine derivatives. The aim of this study was to explore the biodistribution, tumor uptake, kidney localization, and stability characteristics of these new analogs in order to develop new diagnostic tools for exocrine pancreatic cancer. Four (111)In-labeled DTPA-chelated NT analogs and one (111)In-labeled DOTA-chelated NT analog were evaluated in NMRI nude mice bearing NT receptor-positive HT29 tumors. Experiments with a coinjection of unlabeled NT or lysine were performed to investigate receptor-mediated uptake and kidney protection, respectively. In addition, the in vivo serum stability of the most promising analog was analyzed. In the biodistribution study in mice, at 4 hours postinjection, a low percentage of the injected dose per gram (%ID/g) of tissue for all compounds was found in NT receptor-negative organs, such as the blood, spleen, pancreas, liver, muscle, and femur. A high uptake was found in the colon, intestine, kidneys, and in implanted HT29 tumors. The coinjection of excess unlabeled neurotensin significantly reduced tumor uptake, showing tumor uptake to be receptor-mediated. To a lesser extent, this was also observed for the colon, but not for other tissues. We concluded that DTPA-(Pip)Gly-Pro-(PipAm)Gly-Arg-Pro-Tyr-tBuGly-Leu-OH and the DOTA-linked counterpart have the most favorable biodistribution properties regarding tumor uptake.
Insights
New neurotensin (NT) analogs show promising tumor uptake for diagnosing pancreatic cancer. These stable analogs demonstrate receptor-mediated accumulation in tumors, aiding in the development of novel diagnostic tools.
Area of Science:
- Oncology
- Radiochemistry
- Molecular Imaging
Background:
- Neurotensin (NT) receptors are frequently overexpressed in human tumors, including pancreatic ductal adenocarcinoma.
- Developing targeted diagnostic tools for exocrine pancreatic cancer is crucial due to receptor overexpression.
Purpose of the Study:
- To evaluate the biodistribution, tumor uptake, kidney localization, and stability of novel, stable neurotensin analogs.
- To assess the potential of these analogs as diagnostic agents for exocrine pancreatic cancer.
Main Methods:
- Synthesis of new stable neurotensin analogs with high receptor affinity.
- (111)In-labeling of DTPA- and DOTA-chelated NT analogs.
- Biodistribution studies in NMRI nude mice bearing HT29 tumors, including receptor-mediated uptake and kidney protection experiments.
Main Results:
- All evaluated compounds showed low uptake in NT receptor-negative organs.
- High uptake was observed in HT29 tumors, colon, and intestine, indicating receptor-mediated tumor targeting.
- DTPA-(Pip)Gly-Pro-(PipAm)Gly-Arg-Pro-Tyr-tBuGly-Leu-OH and its DOTA-linked counterpart exhibited favorable biodistribution for tumor uptake.
Conclusions:
- The novel neurotensin analogs demonstrate effective receptor-mediated tumor uptake.
- These analogs hold significant potential for the development of advanced diagnostic tools for exocrine pancreatic cancer.
- Further investigation into these analogs could lead to improved imaging and early detection strategies.
