uu.seUppsala universitets publikationer
Ändra sökning
RefereraExporteraLänk till posten
Permanent länk

Direktlänk
Referera
Referensformat
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Annat format
Fler format
Språk
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Annat språk
Fler språk
Utmatningsformat
  • html
  • text
  • asciidoc
  • rtf
High Contrast PET Imaging of GRPR Expression in Prostate Cancer Using Cobalt-Labeled Bombesin Antagonist RM26
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för Molekylär Avbildning.
Odense University Hospital, PET & Cyclotron Unit, Department of Nuclear Medicine; University of Southern Denmark, Department of Clinical Research.
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
Odense University Hospital, PET & Cyclotron Unit, Department of Nuclear Medicine.
Visa övriga samt affilieringar
2017 (Engelska)Ingår i: Contrast Media & Molecular Imaging, ISSN 1555-4309, E-ISSN 1555-4317, artikel-id UNSP 6873684Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

High gastrin releasing peptide receptor (GRPR) expression is associated with numerous cancers including prostate and breast cancer. The aim of the current study was to develop a Co-55-labeled PET agent based on GRPR antagonist RM26 for visualization of GRPR-expressing tumors. Labeling with Co-57 and Co-55, stability, binding specificity, and in vitro and in vivo characteristics of Co-57-NOTA-PEG(2)-RM26 were studied. NOTA-PEG(2)-RM26 was successfully radiolabeled with Co-57 and Co-55 with high yields and demonstrated high stability. The radiopeptide showed retained binding specificity to GRPR in vitro and in vivo. Co-57-NOTA-PEG(2)-RM26 biodistribution in mice was characterized by rapid clearance of radioactivity from blood and normal non-GRPR-expressing organs and low hepatic uptake. The clearance was predominantly renal with a low degree of radioactivity reabsorption. Tumor-to-blood ratios were approximately 200 (3 h pi) and 1000 (24 h pi). The favorable biodistribution of cobalt-labeled NOTA-PEG(2)-RM26 translated into high contrast preclinical PET/CT (using Co-55) and SPECT/CT (using Co-57) images of PC-3 xenografts. The initial biological results suggest that Co-55-NOTA-PEG(2)-RM26 is a promising tracer for PET visualization of GRPR-expressing tumors.

Ort, förlag, år, upplaga, sidor
2017. artikel-id UNSP 6873684
Nyckelord [en]
Positron-Emission-Tomography, Receptor-Positive Tumors, In-Vivo Evaluation, Radiolabeled Peptides, Analog; Agonists, Visualization, Proteins, Affinity, Therapy.
Nationell ämneskategori
Radiologi och bildbehandling
Identifikatorer
URN: urn:nbn:se:uu:diva-334114DOI: 10.1155/2017/6873684ISI: 000408099300001OAI: oai:DiVA.org:uu-334114DiVA, id: diva2:1160212
Forskningsfinansiär
Cancerfonden, CAN2014/474; CAN2015/350Vetenskapsrådet, 2015-02509; 2015-02353Knut och Alice Wallenbergs StiftelseScience for Life Laboratory - a national resource center for high-throughput molecular bioscienceTillgänglig från: 2017-11-24 Skapad: 2017-11-24 Senast uppdaterad: 2019-07-17Bibliografiskt granskad
Ingår i avhandling
1. Prostate cancer theranostics using GRPR antagonist RM26
Öppna denna publikation i ny flik eller fönster >>Prostate cancer theranostics using GRPR antagonist RM26
2019 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

The malignant transformation of cells is often associated with an alteration of their molecular phenotype, resulting in overexpression of several cell surface proteins. Gastrin-releasing peptide receptor (GRPR) and prostate-specific membrane antigen (PSMA) are examples of such pro-teins that are expressed at a high density in prostate cancer. GRPR is primarily expressed in earlier stages of prostate cancer and tends to decrease with disease progression. This expression pattern indicates that GRPR could be a promising target for imaging and treatment of oligometa-static prostate cancer, an early step in prostate cancer progression characterized by limited meta-static spread. In contrast, the expression of PSMA increases with cancer progression and is significantly upregulated as tumors dedifferentiate into higher grade, in androgen-insensitive and metastatic lesions.

This thesis is based on five original articles (papers I-V) and focuses on the preclinical de-velopment of radiotracers for imaging and treatment of prostate cancer. The work can be divided into three distinct parts: (1) the development and optimization of GRPR-antagonist RM26 for high contrast PET and SPECT imaging of oligometastatic prostate cancer (papers I-III), (2) the preclinical evaluation of 177Lu-labeled RM26 as a potential candidate for peptide receptor radionuclide therapy (PRRT) in GRPR-expressing tumors, alone or in combination with anti-HER2 antibody trastuzumab (paper IV), and (3) the development of a bispecific heterodimer targeting both PSMA and GRPR in prostate cancer (paper V).

We have demonstrated that the in vitro and in vivo properties of GRPR antagonist RM26 are strongly influenced by the choice of chelator-radionuclide complex and that long-lived radionuclides are desirable for high-contrast imaging. Furthermore, our data indicate that 55Co-NOTA-PEG2-RM26 has remarkable potential for next-day high-contrast PET imaging of GRPR-expressing tumors. Experimental PRRT using 177Lu-DOTAGA-PEG2-RM26 resulted in a pronounced inhibition of tumor growth and a significantly longer median survival. Interestingly, survival was further improved when trastuzumab was co-injected with 177Lu-DOTAGA-PEG2-RM26. These data indicate that blocking HER2 with trastuzumab decreased the repairing ability of irradiated cells. Finally, we developed a heterodimer (NOTA-DUPA-RM26) for imaging GRPR and PSMA expression in prostate cancer shortly after administration.

In conclusion, we have successfully developed and preclinically evaluated radioconjugates for GRPR-directed theranostics in oligometastatic prostate cancer using the bombesin antagonistic analog RM26.

Ort, förlag, år, upplaga, sidor
Uppsala: Acta Universitatis Upsaliensis, 2019. s. 80
Serie
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 274
Nyckelord
Gastrin-releasing peptide receptor (GRPR), Bombesin, Prostate-specific membrane antigen (PSMA), Antagonist, Radionuclide molecular imaging, Theranostics, Peptide receptor radionuclide therapy (PRRT).
Nationell ämneskategori
Läkemedelskemi
Identifikatorer
urn:nbn:se:uu:diva-389563 (URN)978-91-513-0695-7 (ISBN)
Disputation
2019-09-14, Rudbecksalen, Rudbecklaboratoriet, Dag Hammarskjölds väg 20, Uppsala, 10:00 (Engelska)
Opponent
Handledare
Tillgänglig från: 2019-08-23 Skapad: 2019-07-17 Senast uppdaterad: 2019-09-17

Open Access i DiVA

fulltext(2997 kB)97 nedladdningar
Filinformation
Filnamn FULLTEXT01.pdfFilstorlek 2997 kBChecksumma SHA-512
83bb2503e36b18ac17b6fee4cdde02c85b958c81949121c4d46eeaae7c002fd9a90e923e38c3ec76fa7edf770af09b21106389ea00578d0b11934b69422e88c3
Typ fulltextMimetyp application/pdf

Övriga länkar

Förlagets fulltext

Personposter BETA

Mitran, BogdanRosenström, UlrikaLarhed, MatsTolmachev, VladimirOrlova, Anna

Sök vidare i DiVA

Av författaren/redaktören
Mitran, BogdanRosenström, UlrikaLarhed, MatsTolmachev, VladimirOrlova, Anna
Av organisationen
Avdelningen för Molekylär AvbildningAvdelningen för organisk farmaceutisk kemiScience for Life Laboratory, SciLifeLabMedicinsk strålningsvetenskap
I samma tidskrift
Contrast Media & Molecular Imaging
Radiologi och bildbehandling

Sök vidare utanför DiVA

GoogleGoogle Scholar
Totalt: 97 nedladdningar
Antalet nedladdningar är summan av nedladdningar för alla fulltexter. Det kan inkludera t.ex tidigare versioner som nu inte längre är tillgängliga.

doi
urn-nbn

Altmetricpoäng

doi
urn-nbn
Totalt: 423 träffar
RefereraExporteraLänk till posten
Permanent länk

Direktlänk
Referera
Referensformat
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Annat format
Fler format
Språk
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Annat språk
Fler språk
Utmatningsformat
  • html
  • text
  • asciidoc
  • rtf