Synthesis and preclinical evaluation of radio-iodinated GRPR/PSMA bispecific heterodimers for the theranostics application in prostate cancer

Ayman Abouzayed, Cheng Bin Yim, Bogdan Mitran, Sara S. Rinne, Mats Larhed, Ulrika Rosenström, Anna Orlova, Anna Orlova

Research output: Contribution to journalArticlepeer-review

5 Citations (Scopus)

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 expressionincreaseswithprogression. Thepossibility of targeting bothmarkerswitha 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-BO530was 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.

Original languageEnglish
Article number358
JournalPharmaceutics
Volume11
Issue number7
DOIs
Publication statusPublished - Jul 2019
Externally publishedYes

Keywords

  • bispecific heterodimers
  • GRPR
  • prostate cancer
  • PSMA
  • radio-iodine
  • theranostics

ASJC Scopus subject areas

  • Pharmaceutical Science

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