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Synthesis and Preclinical Evaluation of Radio-Iodinated GRPR/PSMA Bispecific Heterodimers for the Theranostics Application in Prostate Cancer
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Theranostics.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Theranostics.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Theranostics.ORCID iD: 0000-0001-7921-3268
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Theranostics.
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2019 (English)In: Pharmaceutics, ISSN 1999-4923, E-ISSN 1999-4923, Vol. 11, no 7, article id 358Article in journal (Refereed) Published
Abstract [en]

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. [I-125]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 [I-125]I-BO530 demonstrated in vivo specificity to both targets. A biodistribution study of [I-125]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 [I-125]I-BO530 is a promising agent for theranostics application in prostate cancer.

Place, publisher, year, edition, pages
2019. Vol. 11, no 7, article id 358
Keywords [en]
prostate cancer, GRPR, PSMA, bispecific heterodimers, theranostics, radio-iodine
National Category
Cancer and Oncology
Identifiers
URN: urn:nbn:se:uu:diva-393138DOI: 10.3390/pharmaceutics11070358ISI: 000478995100060PubMedID: 31340483OAI: oai:DiVA.org:uu-393138DiVA, id: diva2:1353422
Funder
Swedish Research Council, 2015-02509Swedish Research Council, 2015-02353Swedish Cancer Society, CAN 2017/425Swedish Cancer Society, CAN2015/350Swedish Cancer Society, CAN 2018/436Available from: 2019-09-23 Created: 2019-09-23 Last updated: 2019-09-23Bibliographically approved

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Abouzayed, AymanMitran, BogdanRinne, Sara S.Tolmachev, VladimirLarhed, MatsRosenström, UlrikaOrlova, Anna

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