Open Collections

Wang, Lei

University of British Columbia

Gastrin-releasing peptide receptor (GRPR) is overexpressed in multiple cancers, making it a promising target for diagnosis and therapy. However, most clinically evaluated GRPR-targeted radiopharmaceuticals show high accumulation in the pancreas and limited metabolic stability, which may restrict their diagnostic and therapeutic applications. This dissertation focuses on developing radiolabeled GRPR-targeting ligands with reduced pancreas uptake and improved metabolic stability to enhance diagnostic and therapeutic efficacy for GRPR-expressing tumors. Inspired by a series of GRPR antagonists published by Schally’s group, we first developed four radiolabeled GRPR antagonists based on the [Leu¹³ψThz¹⁴]Bombesin(7-14) sequence and three radiolabeled GRPR agonists by restoring the reduced peptide bond between residues 13-14 (Leu¹³ψThz¹⁴) in the [Leu¹³ψThz¹⁴]Bombesin(7-14) sequence with a normal amide bond. The antagonist [⁶⁸Ga]Ga-TacsBOMB2 and agonist [⁶⁸Ga]Ga-TacBOMB2 showed good tumor uptake and minimal pancreas uptake. Then we modified our lead agonist and antagonist candidates (TacBOMB2 and TacsBOMB2) with unnatural amino acid substitution to strengthen the bonds at the potential cleavage sites of neutral endopeptidase (NEP) to improve the stability. Our findings indicate that the Tle¹⁰ and NMe-His¹² substitutions markedly improve the stability of the GRPR agonist TacBOMB2 without affecting its binding affinity. Though, with no significant improvement in stability, NMe-Gly¹¹ substitution was shown to improve the tumor uptake and provide a better tumor-to-background contrast ratios for [⁶⁸Ga]Ga-TacsBOMB5 derived from TacsBOMB2. Then we labeled our lead candidates with ¹⁷⁷Lu for further evaluations. However, shorter tumor retention and lower absorbed radiation doses in PC-3 tumor xenograft were observed for all our ¹⁷⁷Lu-labeled GRPR-targeted ligands compared with the clinically validated [¹⁷⁷Lu]Lu-RM2, indicating further optimizations are still needed to prolong the tumor retention for therapeutic applications. To avoid the oxidation of Thz, we replaced the Thz¹⁴ with Pro¹⁴ to potentially prolong the shelf-life of our top GRPR-targeted radiopharmaceuticals. GRPR antagonist, [⁶⁸Ga]Ga-ProBOMB5 (DOTA-Pip-[DPhe⁶,NMe-Gly¹¹,Leu¹³ψPro¹⁴]Bombesin(6-14)), showed great tumor uptake, minimal accumulation in pancreas, and excellent tumor-to-background contrast ratios among all the novel GRPR-targeted tracers in this dissertation. Our results are encouraging to support clinical translation of [⁶⁸Ga]Ga-ProBOMB5 as a diagnostic radiotracer for detecting GRPR-expressing lesions, particularly the lesions in or adjacent to the pancreas.

Text

2025-03-19

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/90509

Interdisciplinary Oncology

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/