In vivo investigation of Gallium-68 and Bismuth-205/206 labeled beta cyclodextrin for targeted alpha therapy of prostaglandin E2 receptor-expressing tumors in mice

Katalin Csige; Judit P Szabó; Ibolya Kálmán-Szabó; Noémi S Dénes; Dezső Szikra; Zita Képes; Gábor Opposits; Gábor Méhes; István Kertész; Ferenc Fenyvesi; György Trencsényi; István Hajdu

doi:10.1016/j.ijpharm.2022.122132

In vivo investigation of Gallium-68 and Bismuth-205/206 labeled beta cyclodextrin for targeted alpha therapy of prostaglandin E2 receptor-expressing tumors in mice

Int J Pharm. 2022 Sep 25:625:122132. doi: 10.1016/j.ijpharm.2022.122132. Epub 2022 Aug 24.

Affiliations

¹ Division of Nuclear Medicine and Translational Imaging, Department of Medical Imaging, Faculty of Medicine, University of Debrecen, Nagyerdei St. 98, H-4032 Debrecen, Hungary; Doctoral School of Pharmaceutical Sciences, University of Debrecen, Nagyerdei St. 98, H-4032 Debrecen, Hungary.
² Division of Nuclear Medicine and Translational Imaging, Department of Medical Imaging, Faculty of Medicine, University of Debrecen, Nagyerdei St. 98, H-4032 Debrecen, Hungary.
³ Department of Pathology, Faculty of Medicine, University of Debrecen, Nagyerdei St. 98, H-4032 Debrecen, Hungary.
⁴ Department of Pharmaceutical Technology, Faculty of Pharmacy, University of Debrecen, Nagyerdei St. 98, H-4032 Debrecen, Hungary.
⁵ Division of Nuclear Medicine and Translational Imaging, Department of Medical Imaging, Faculty of Medicine, University of Debrecen, Nagyerdei St. 98, H-4032 Debrecen, Hungary; Doctoral School of Pharmaceutical Sciences, University of Debrecen, Nagyerdei St. 98, H-4032 Debrecen, Hungary. Electronic address: hajdu.istvan@med.unideb.hu.

PMID: 36028082
DOI: 10.1016/j.ijpharm.2022.122132

Abstract

Prostaglandin E2 (PGE2) molecule and its receptors play an important role in the development of malignancies and metastases therefore PGE2 may play a crucial role in the diagnosis and a new therapeutic target in the field of radionuclide therapy of PGE2-positive tumors. PGE2 form complexes with RAMEB (randomly-methylated-beta-cyclodextrin) with high affinity therefore the aim of this present study was to synthesize a PGE2-specific DOTAGA-RAMEB, which can be labeled with diagnostic and therapeutic isotopes also and binds to PGE2-positive tumors. DOTAGA-RAMEB was labeled with ⁶⁸Ga and ^205/206Bi radionuclides and their radiochemical purity (RCP%), partition coefficient (logP values), and in vitro and in vivo stability were determined. For the assessment of the biological properties and the PGE2 specificity of [⁶⁸Ga]Ga-DOTAGA-RAMEB and [^205/206Bi]Bi-DOTAGA-RAMEB in vivo PET imaging and ex vivo biodistribution studies were performed using healthy control and PGE2-positive BxPC-3 tumor-bearing CB17 SCID mice. The RCP% of the newly synthesized [⁶⁸Ga]Ga-DOTAGA-RAMEB and [^205/206Bi]Bi-DOTAGA-RAMEB was higher than 98 %. In vivo studies showed that the tumor-to-background ratio of [⁶⁸Ga]Ga-DOTAGA-RAMEB was 2.5 ± 0.2 as a result BxPC-3 tumors were clearly identified on PET images. Beside this the ex vivo biodistribution studies showed that the accumulation rate of [⁶⁸Ga]Ga-DOTAGA-RAMEB and [^205/206Bi]Bi-DOTAGA-RAMEB was similar in the PGE2-positive BxPC-3 tumors.

Keywords: Cyclodextrin; Pancreas adenocarcinoma; Prostaglandin E2; Radiotherapy; Targeted alpha therapy.

MeSH terms

Animals
Bismuth
Cell Line, Tumor
Dinoprostone / metabolism
Gallium Radioisotopes / chemistry
Mice
Mice, SCID
Neoplasms* / drug therapy
Positron-Emission Tomography
Radioisotopes
Receptors, Prostaglandin / metabolism
Receptors, Prostaglandin / therapeutic use
Tissue Distribution
beta-Cyclodextrins* / chemistry

Substances

Bismuth-205
Gallium Radioisotopes
Radioisotopes
Receptors, Prostaglandin
beta-Cyclodextrins
Gallium-68
Dinoprostone
Bismuth