In Vivo Enzyme Inhibition Improves the Targeting of [¹⁷⁷Lu]DOTA-GRP(13–27) in GRPR-Positive Tumors in Mice

Abstract

Coadministration of PA significantly increased the percentage of intact radiopeptide in the mouse circulation. From biodistribution and ex vivo autoradiography studies, coadministration of both lysine and PA with [(177)Lu]DOTA-GRP(13-27) appeared to induce a clear improvement of tumor uptake as well as lower levels of renal radioactivity, causing a promising ninefold increase in tumor/kidney ratios.

Bombesin related peptides/receptors and their promising therapeutic roles in cancer imaging, targeting and treatment

“…In addition, radiolabeled-BnR-agonists/antagonists have been co-administered with neutral endopeptidase inhibitors, which are one of the major proteolytic enzymes for Bn related peptides[81], which has resulted in enhanced uptake in tumor xenografts.…”

“…A number of recent studies using various radiolabeled( 188 Re, 55/57 Co, 111 In, 64 Cu, 99M Tc, 68 Ga, 18 F) BnR-agonists(primarily-GRPR-agonists) show imaging[16•,73,74,100,121,145,146,147•,148–155] or targeted-tumoral delivery of cytotoxic-radioisotopes( 177 Lu, 188 Re, 111 In, 64 Cu, 18 F)[16,74,77,100,147•,154] to prostate-cancer-cells both in vitro [16,73,74,81,121,145–147•,149,152–155] and in vivo to image prostate-cancer xenografts in nude-mice[16•,73,74,77,81,100,121,145,146,147•,148,149,151–155]. In two comparative studies in vivo of xenografts of the prostate-cancer-cell-line[155,156], PC-3, in nude-mice, a 68 Ga-labeled-BnR-agonist or 18 F-labeled-Bn-antagonist(BAY 86-4367) showed greater tumor-uptake with lower background than a metabolic probe, which is increasingly used in prostate-cancer patients.…”

“…A BnR-agonist conjugated to DUPA(small molecule, PSMA-targeting-probe) radiolabeled-with 64 Cu to allow PET imaging, as well as a BnR-agonist conjugated to a PSMA inhibitor, Glu-urea-Lys(Ahx)-HBED-CC, which allowed targeting to both BnR’s and PSMA which are frequently overexpressed by prostate cancers, demonstrates excellent imaging and targeting to prostate-cancer-xenografts in nude-mice[73] and enhanced affinity for prostate-cancer-cells both in vitro and for xenografts in vivo . Another approach with prostate-cancer to increase the tumor-uptake of the BnR probe is to co-administer a neutral-endopeptidase inhibitor, because this is one of the main proteolytic enzymes for Bn-related-peptides[81]. This approach with both a radiolabeled-BnR-antagonist/agonist[81], increased the uptake of the radiolabeled-ligand in prostate-cancer-xenografts.…”

“…Another approach with prostate-cancer to increase the tumor-uptake of the BnR probe is to co-administer a neutral-endopeptidase inhibitor, because this is one of the main proteolytic enzymes for Bn-related-peptides[81]. This approach with both a radiolabeled-BnR-antagonist/agonist[81], increased the uptake of the radiolabeled-ligand in prostate-cancer-xenografts.…”

Molecular imaging in neuroendocrine tumors: recent advances, controversies, unresolved issues, and roles in management

“…In one study of 7 patients refractory to 90 Y/ 177 Lu-DOTATATE, all demonstrated enduring responses with favorable acute and midterm toxicity with 213 Bi-DOTATOC[104]. Other approaches being taken to increase the cytotoxicity of 90 Y-/ 177 Lu in PRRT include the use of combination therapies including using 90 Y-/ 177 Lu-DOTATATE together[105]; combined with PARP inhibitors to potentiate the accummulation of double-stranded DNA breaks and cytoxicity[106]; with peptide-degradation inhibitors such as phosphoramidon to increase tissue uptake[107, 108] or with chemotherapeutics to increase sensitivity such as temozolomide, or capecitabine and other anti-tumor agents such as everolimus[30, 109–112]. …”