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- Title
Synthesis and Preclinical Evaluation of Radio-Iodinated GRPR/PSMA Bispecific Heterodimers for the Theranostics Application in Prostate Cancer.
- Authors
Abouzayed, Ayman; Yim, Cheng-Bin; Mitran, Bogdan; Rinne, Sara S.; Tolmachev, Vladimir; Larhed, Mats; Rosenström, Ulrika; Orlova, Anna
- Abstract
Gastrin-releasing peptide receptor (GRPR) and prostate-specific membrane antigen (PSMA) are overexpressed in most prostate cancers. GRPR expression is higher in early stages while PSMA expression increases with progression. The possibility of targeting both markers with a single theranostics radiotracer could improve patient management. Three GRPR/PSMA-targeting bispecific heterodimers (urea derivative PSMA-617 and bombesin-based antagonist RM26 linked via X-triazolyl-Tyr-PEG2, X = PEG2 (BO530), (CH2)8 (BO535), none (BO536)) were synthesized by solid-phase peptide synthesis. Peptides were radio-iodinated and evaluated in vitro for binding specificity, cellular retention, and affinity. In vivo specificity for all heterodimers was studied in PC-3 (GRPR-positive) and LNCaP (PSMA-positive) xenografts. [125I]I-BO530 was evaluated in PC-3pip (GRPR/PSMA-positive) xenografts. Micro single-photon emission computed tomography/computed tomography (microSPECT/CT) scans were acquired. The heterodimers were radiolabeled with high radiochemical yields, bound specifically to both targets, and demonstrated high degree of activity retention in PC-3pip cells. Only [125I]I-BO530 demonstrated in vivo specificity to both targets. A biodistribution study of [125I]I-BO530 in PC-3pip xenografted mice showed high tumor activity uptake (30%–35%ID/g at 3 h post injection (pi)). Activity uptake in tumors was stable and exceeded all other organs 24 h pi. Activity uptake decreased only two-fold 72 h pi. The GRPR/PSMA-targeting heterodimer [125I]I-BO530 is a promising agent for theranostics application in prostate cancer.
- Subjects
SINGLE-photon emission computed tomography; UREA derivatives; PROSTATE cancer; HETERODIMERS; COMPANION diagnostics; PEPTIDE receptors; SOLID-phase synthesis
- Publication
Pharmaceutics, 2019, Vol 11, Issue 7, p358
- ISSN
1999-4923
- Publication type
Article
- DOI
10.3390/pharmaceutics11070358