| Title: |
Paving the Way for CCK2R-Targeted Peptide Receptor Radionuclide Therapy with [177Lu]Lu-DOTA-MGS5 in Patients with Small Cell Lung Cancer |
| Authors: |
Taraneh Sadat Zavvar; Giulia Santo; Leonhard Gruber; Ariane Kronthaler; Judith Hagenbuchner; Ira Skvortsova; Inken Piro; Katja Steiger; Vladan Martinovic; Danijela Minasch; Judith Löffler-Ragg; Gianpaolo di Santo; Irene J. Virgolini; Elisabeth von Guggenberg |
| Source: |
Pharmaceutics ; Volume 18 ; Issue 1 ; Pages: 138 |
| Publisher Information: |
Multidisciplinary Digital Publishing Institute |
| Publication Year: |
2026 |
| Collection: |
MDPI Open Access Publishing |
| Subject Terms: |
peptide receptor radionuclide therapy; cholecystokinin-2 receptor; minigastrin; SPECT/CT imaging; first-in-human |
| Description: |
Background/Objectives: Peptide receptor radionuclide therapy (PRRT) is an established treatment for neuroendocrine tumors (NETs), enabling targeted radiation delivery via radiolabeled peptides. Small cell lung cancer (SCLC) remains a major therapeutic challenge due to its aggressive nature and poor prognosis. Despite advances, relapse rates are high and effective therapies are limited. We previously demonstrated the diagnostic potential of the cholecystokinin-2 receptor (CCK2R)-targeting minigastrin analog [68Ga]Ga-DOTA-MGS5 in PET/CT imaging of different NETs. Building on this, we developed and evaluated [177Lu]Lu-DOTA-MGS5 as a therapeutic PRRT agent. Methods: Preclinical studies investigating the receptor-mediated cellular internalization and intracellular distribution over time in A431 cells with and without CCK2R expression were performed using the fluorescent tracer ATTO-488-MGS5. Short- and long-term cytotoxic effects of [177Lu]Lu-DOTA-MGS5 were evaluated on the same cell line using trypan blue exclusion and clonogenic survival assays. CCK2R expression was assessed by immunohistochemistry in 42 SCLC tissue specimens. In addition, the first PRRT with [177Lu]Lu-DOTA-MGS5 was conducted in a patient with extensive disease SCLC (ED-SCLC) after confirming CCK2R-positive uptake in [68Ga]Ga-DOTA-MGS5 PET/CT. Results: Rapid binding and internalization into A431-CCK2R cells, with progressive accumulation in intracellular compartments, was observed for ATTO-488-MGS5. Short-term irradiation effects of [177Lu]Lu-DOTA-MGS5 were comparable for 4 h and 24 h incubation and were between the effects obtained with 2 and 4 Gy of external beam radiotherapy (EBRT). Clonogenic survival of A431-CCK2R cells incubated with increasing activity of [177Lu]Lu-DOTA-MGS5 decreased in a dose-dependent manner. Immunohistochemistry on SCLC specimens confirmed moderate to high CCK2R expression in 16 out of 42 SCLC samples. In the first patient with SCLC treated with four cycles of [177Lu]Lu-DOTA-MGS5 with a total activity of 17.2 GBq, an ... |
| Document Type: |
text |
| File Description: |
application/pdf |
| Language: |
English |
| Relation: |
Clinical Pharmaceutics; https://dx.doi.org/10.3390/pharmaceutics18010138 |
| DOI: |
10.3390/pharmaceutics18010138 |
| Availability: |
https://doi.org/10.3390/pharmaceutics18010138 |
| Rights: |
https://creativecommons.org/licenses/by/4.0/ |
| Accession Number: |
edsbas.92C38C49 |
| Database: |
BASE |