Next Article in Journal
Effective Therapeutic Delivery and Bioavailability Enhancement of Pioglitazone Using Drug in Adhesive Transdermal Patch
Next Article in Special Issue
Beyond the Barrier: Targeted Radionuclide Therapy in Brain Tumors and Metastases
Previous Article in Journal
Vitamin E-Loaded PLA- and PLGA-Based Core-Shell Nanoparticles: Synthesis, Structure Optimization and Controlled Drug Release
Previous Article in Special Issue
Comparative Radioimmunotherapy of Experimental Melanoma with Novel Humanized Antibody to Melanin Labeled with 213Bismuth and 177Lutetium
Open AccessArticle

Synthesis and Preclinical Evaluation of Radio-Iodinated GRPR/PSMA Bispecific Heterodimers for the Theranostics Application in Prostate Cancer

1
Department of Medicinal Chemistry, Uppsala University, 75183 Uppsala, Sweden
2
Department of Immunology, Genetics and Pathology, Uppsala University, 75183 Uppsala, Sweden
3
Science for Life Laboratory, Uppsala University, 75183 Uppsala, Sweden
*
Author to whom correspondence should be addressed.
Pharmaceutics 2019, 11(7), 358; https://doi.org/10.3390/pharmaceutics11070358
Received: 15 June 2019 / Revised: 16 July 2019 / Accepted: 20 July 2019 / Published: 23 July 2019
(This article belongs to the Special Issue Targeted Radionuclide Tumor Therapy)
  |  
PDF [4962 KB, uploaded 23 July 2019]
  |  

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. View Full-Text
Keywords: prostate cancer; GRPR; PSMA; bispecific heterodimers; theranostics; radio-iodine prostate cancer; GRPR; PSMA; bispecific heterodimers; theranostics; radio-iodine
Figures

Graphical abstract

This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).
SciFeed

Share & Cite This Article

MDPI and ACS Style

Abouzayed, A.; Yim, C.-B.; Mitran, B.; Rinne, S.S.; Tolmachev, V.; Larhed, M.; Rosenström, U.; Orlova, A. Synthesis and Preclinical Evaluation of Radio-Iodinated GRPR/PSMA Bispecific Heterodimers for the Theranostics Application in Prostate Cancer. Pharmaceutics 2019, 11, 358.

Show more citation formats Show less citations formats

Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Related Articles

Article Metrics

Article Access Statistics

1

Comments

[Return to top]
Pharmaceutics EISSN 1999-4923 Published by MDPI AG, Basel, Switzerland RSS E-Mail Table of Contents Alert
Back to Top