Enhanced Retention of NTSR1-Targeted Radionuclide Therapeutics via Covalent Inhibitors in Pancreatic, Colorectal, and Prostate Cancer Models

作者：Wenting Zhang, Wei Fan, Katie Brake, Alireza Basiri, Megan Hyun, Lynette M. Smith, Subodh M. Lele, Abhijit Aithal, Maneesh Jain, Jered C. Garrison · 发表于：Molecular Pharmaceutics · 年份：2025 · DOI：10.1021/acs.molpharmaceut.4c01324 · 被引用次数：10 · 研究领域：Radiopharmaceutical Chemistry and Applications、Peptidase Inhibition and Analysis、Estrogen and related hormone effects

Neurotensin receptor subtype 1 (NTSR1) is overexpressed in numerous cancers. Our laboratory is exploring the utilization of covalent cysteine protease inhibitors (e.g., E-64) to increase tumor retention of targeted radionuclide therapeutics (TRTs) through protein adduct formation. Using this approach, we reported [ 177 Lu]Lu-NA-ET1, an NTSR1-targeted construct. In this work, we continue the exploration of [ 177 Lu]Lu-NA-ET1 in three different NTSR1-positive cancer models. [ 177 Lu]Lu-3BP-227, a clinically investigated NTSR1-targeted construct, was utilized as a comparative benchmark. Both [ 177 Lu]Lu-NA-ET1 and [ 177 Lu]Lu-3BP-227 underwent in vitro investigation, including internalization and autoradiographic sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) studies, in NTSR1-positive AsPC-1, HT-29, and PC-3 cell lines. Biodistribution, human radiation dosimetry, and in vivo autoradiographic SDS-PAGE studies were performed by using the same models. A dose escalation study using 585 MBq (15.8 mCi) of [ 177 Lu]Lu-NA-ET1 was implemented in immunocompetent CF-1 mice. In all three cell lines, [ 177 Lu]Lu-NA-ET1 demonstrated similar cellular uptake profiles relative to those of [ 177 Lu]Lu-3BP-227. Biodistribution studies of [ 177 Lu]Lu-NA-ET1 revealed increased (1.9–4.4-fold) tumor retention and radiation dose delivery relative to the control. Analysis of the in vitro and in vivo cellular and tissue lysates showed protein adducts that ranged from approximately ...