Nuclear medicine and biology · 2025
Comparative evaluation of radiolabeled bombesin analogs [177Lu]Lu-AMBA and [177Lu]Lu-RM2 for targeting GRPR in glioblastoma model.
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Grzmil Michal, Spahn Muriel Aline, Berger Philipp, Schibli Roger, Béhé Martin
Аннотация
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 [177Lu]Lu-AMBA and antagonist [177Lu]Lu-RM2 was evaluated through internalization assays in human GBM U-251 and breast cancer T47-D 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 U-251 xenografted nude mice.
RESULTS: Both [177Lu]Lu-AMBA and [177Lu]Lu-RM2 showed GRPR-specific uptake, whereby [177Lu]Lu-AMBA was internalized in contrast to [177Lu]Lu-RM2, which remained bound to the cell membrane. In vitro studies showed no significant difference in the total cellular uptake of radiopeptides. [177Lu]Lu-RM2 binding to the receptor was blocked by the unlabeled AMBA ligand. Quantification of [177Lu]Lu-AMBA and [177Lu]Lu-RM2-induced DSB and ROS levels revealed no significant difference in treated cells. In vivo, biodistribution showed increased tumor uptake of [177Lu]Lu-RM2 compared to [177Lu]Lu-AMBA, whereby washout from receptor positive organs like pancreas, intestine, stomach, and spleen were significantly faster in [177Lu]Lu-RM2-treated mice.
CONCLUSION: This study established targeting GRPR with both agonist and antagonist radioligands in glioma U-251 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.
METHODS: The cellular uptake of lutetium-177 labeled agonist [177Lu]Lu-AMBA and antagonist [177Lu]Lu-RM2 was evaluated through internalization assays in human GBM U-251 and breast cancer T47-D 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 U-251 xenografted nude mice.
RESULTS: Both [177Lu]Lu-AMBA and [177Lu]Lu-RM2 showed GRPR-specific uptake, whereby [177Lu]Lu-AMBA was internalized in contrast to [177Lu]Lu-RM2, which remained bound to the cell membrane. In vitro studies showed no significant difference in the total cellular uptake of radiopeptides. [177Lu]Lu-RM2 binding to the receptor was blocked by the unlabeled AMBA ligand. Quantification of [177Lu]Lu-AMBA and [177Lu]Lu-RM2-induced DSB and ROS levels revealed no significant difference in treated cells. In vivo, biodistribution showed increased tumor uptake of [177Lu]Lu-RM2 compared to [177Lu]Lu-AMBA, whereby washout from receptor positive organs like pancreas, intestine, stomach, and spleen were significantly faster in [177Lu]Lu-RM2-treated mice.
CONCLUSION: This study established targeting GRPR with both agonist and antagonist radioligands in glioma U-251 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.