Comparative evaluation of radiolabeled bombesin analogs [177Lu]Lu-AMBA and [177Lu]Lu-RM2 for targeting GRPR in glioblastoma model
Bibliographic record
Abstract
Introduction Radiolabeled agonist ligands bind to and activate target receptors, inducing internalization and delivering radionuclides into the inner cancer cells. In contrast, receptor-bound antagonizing radiopeptides inhibit receptor signaling and remain outside of the cells, but often show more favorable pharmacokinetics. Our head-to-head preclinical comparison of the gastrin-releasing peptide receptor (GRPR) antagonist and the agonist radioligands was conducted in a human glioblastoma (GBM) model. Methods The cellular uptake of lutetium-177 labeled agonist [ 177 Lu]Lu-AMBA and antagonist [ 177 Lu]Lu-RM2 was evaluated through internalization assays in human GBM U251 and breast cancer T47D cells. Immunohistochemistry for γH2AX and the 2′,7′-dichlorofluorescein-diacetate (DCFH-DA) probe were used to assess the induction of DNA double strand breaks (DSB) and generation of reactive oxygen species (ROS), respectively. An in vivo biodistribution study of the radiopeptides was conducted using U251 xenografted nude mice. Results : Both [ 177 Lu]Lu-AMBA and [ 177 Lu]Lu-RM2 showed GRPR-specific uptake, whereby [ 177 Lu]Lu-AMBA was internalized in contrast to [ 177 Lu]Lu-RM2, which remained bound to the cell membrane. In vitro studies showed no significant difference in the total cellular uptake of radiopeptides. [ 177 Lu]Lu-RM2 binding to the receptor was blocked by the unlabeled AMBA ligand. Quantification of [ 177 Lu]Lu-AMBA and [ 177 Lu]Lu-RM2-induced DSB and ROS levels revealed no significant difference in treated cells. In vivo , biodistribution showed increased tumor uptake of [ 177 Lu]Lu-RM2 compared to [ 177 Lu]Lu-AMBA, whereby wash-out from receptor positive organs like pancreas, intestine, stomach, and spleen were significantly faster in [ 177 Lu]Lu-RM2-treated mice. Conclusion This study established targeting GRPR with both agonist and antagonist radioligands in glioma U251 in vitro and in vivo models and recommends further development of antagonizing radiolabeled bombesin analog RM2, which showed in vivo superiority in tumor uptake and tumor-to-normal organ ratios (TNRs) over agonist AMBA radioligand.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".