uu.seUppsala universitets publikasjoner
Endre søk
RefereraExporteraLink to record
Permanent link

Direct link
Referera
Referensformat
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Annet format
Fler format
Språk
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Annet språk
Fler språk
Utmatningsformat
  • html
  • text
  • asciidoc
  • rtf
The Effect of Mini-PEG-Based Spacer Length on Binding and Pharmacokinetic Properties of a Ga-68-Labeled NOTA-Conjugated Antagonistic Analog of Bombesin
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Plattformen för preklinisk PET.
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Plattformen för preklinisk PET. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Plattformen för preklinisk PET.
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Plattformen för preklinisk PET.
Vise andre og tillknytning
2014 (engelsk)Inngår i: Molecules, ISSN 1420-3049, E-ISSN 1420-3049, Vol. 19, nr 7, s. 10455-10472Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

The overexpression of gastrin-releasing peptide receptor (GRPR) in cancer can be used for peptide-receptor mediated radionuclide imaging and therapy. We have previously shown that an antagonist analog of bombesin RM26 conjugated to 1,4,7-triazacyclononane-N, N', N ''-triacetic acid (NOTA) via a diethyleneglycol (PEG(2)) spacer (NOTA-PEG(2)-RM26) and labeled with Ga-68 can be used for imaging of GRPR-expressing tumors. In this study, we evaluated if a variation of mini-PEG spacer length can be used for optimization of targeting properties of the NOTA-conjugated RM26. A series of analogs with different PEG-length (n = 2, 3, 4, 6) was synthesized, radiolabeled and evaluated in vitro and in vivo. The IC50 values of Ga-nat-NOTA-PEG(n)-RM26 (n = 2, 3, 4, 6) were 3.1 +/- 0.2, 3.9 +/- 0.3, 5.4 +/- 0.4 and 5.8 +/- 0.3 nM, respectively. In normal mice all conjugates demonstrated similar biodistribution pattern, however Ga-68-NOTA-PEG(3)-RM26 showed lower liver uptake. Biodistribution of Ga-68-NOTA-PEG(3)-RM26 was evaluated in nude mice bearing PC-3 (prostate cancer) and BT-474 (breast cancer) xenografts. High uptake in tumors (4.6 +/- 0.6% ID/g and 2.8 +/- 0.4% ID/g for PC-3 and BT-474 xenografts, respectively) and high tumor-to-background ratios (tumor/ blood of 44 +/- 12 and 42 +/- 5 for PC-3 and BT-474 xenografts, respectively) were found already at 2 h p.i. of Ga-68-NOTA-PEG(3)-RM26. Results of this study suggest that variation in the length of the PEG spacer can be used for optimization of targeting properties of peptide-chelator conjugates. However, the influence of the mini-PEG length on biodistribution is minor when di-, tri-, tetra- and hexaethylene glycol are compared.

sted, utgiver, år, opplag, sider
2014. Vol. 19, nr 7, s. 10455-10472
Emneord [en]
bombesin analog, PEG, GRPR, antagonist, molecular imaging, breast cancer, prostate cancer, BT-474, PC-3 cells
HSV kategori
Identifikatorer
URN: urn:nbn:se:uu:diva-231315DOI: 10.3390/molecules190710455ISI: 000340036200108PubMedID: 25036155OAI: oai:DiVA.org:uu-231315DiVA, id: diva2:744286
Tilgjengelig fra: 2014-09-08 Laget: 2014-09-07 Sist oppdatert: 2017-12-05bibliografisk kontrollert
Inngår i avhandling
1. Bombesin Antagonists for Targeting Gastrin-Releasing Peptide Receptor-Positive Tumors: Design, Synthesis, Preclinical Evaluation and Optimization of Imaging Agents
Åpne denne publikasjonen i ny fane eller vindu >>Bombesin Antagonists for Targeting Gastrin-Releasing Peptide Receptor-Positive Tumors: Design, Synthesis, Preclinical Evaluation and Optimization of Imaging Agents
2014 (engelsk)Doktoravhandling, med artikler (Annet vitenskapelig)
Abstract [en]

This thesis is focused on the development, preclinical evaluation, and optimization of radiotracers for the detection of gastrin-releasing peptide receptor (GRPR)-expressing tumors. The work is divided into three distinct parts: (1) the development of bombesin (BN) antagonist (RM26)-based imaging radiotracers for the detection of GRPR-expressing tumors using different positron emission tomography (PET) and single photon emission computed tomography (SPECT) radionuclides (68Ga, 18F and 111In), (2) the establishment of a method to monitor the ligand-G protein-coupled receptor (GPCR) interaction in real time without requiring purification and stabilization of the receptors, and (3) the evaluation of radiopeptide structure-related factors (length of mini-PEG linker and composition of chelator for metal labeling) affecting the in vitro and in vivo characteristics of RM26-based tracers.

We demonstrated the possibility of high-contrast in vivo imaging of GRPR-expressing xenografts despite the physiological expression of GRPR in abdominal organs. Fast radioactivity clearance from the blood and healthy organs, including receptor-positive organs, and long retention in the tumors resulted in high tumor-to-background ratios. A novel real-time assay for measuring the kinetics of the radiotracers targeting GPCR was evaluated. Living cells were used instead of purified receptors in this technology, bringing the developmental work one step closer to the true target environment (imaging in living systems). The comparative study of 68Ga-labeled NOTA-PEGn-RM26 with di-, tri-, tetra- and hexaethylene glycol chains demonstrated that the addition of only a few units of ethylene glycol to the spacer is insufficient to appreciably affect the biodistribution of the radiopeptide. Finally, a comparative study of 68Ga-labeled PEG2-RM26 analogs N-terminally conjugated to NOTA, NODAGA, DOTA or DOTAGA highlighted the influence of the chelator on the targeting properties of the radiopeptide.

The main conclusion that can be drawn from this thesis is that 68Ga-NOTA-PEG2-RM26 has favorable biodistribution properties, such as rapid clearance from blood and tissues with physiological GRPR expression levels and long retention in GRPR-expressing tumors, and that this radiopeptide is potentially suitable for initial clinical investigation.

sted, utgiver, år, opplag, sider
Uppsala: Acta Universitatis Upsaliensis, 2014. s. 66
Serie
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 191
Emneord
Bombesin, Gastrin-releasing peptide receptor (GRPR), Antagonist, Radionuclide molecular imaging
HSV kategori
Identifikatorer
urn:nbn:se:uu:diva-232123 (URN)978-91-554-9039-3 (ISBN)
Disputas
2014-10-31, Rudbecksalen, Dag Hammarskjölds väg 20, Uppsala, 09:00 (engelsk)
Opponent
Veileder
Tilgjengelig fra: 2014-10-10 Laget: 2014-09-12 Sist oppdatert: 2018-01-11

Open Access i DiVA

fulltext(560 kB)491 nedlastinger
Filinformasjon
Fil FULLTEXT01.pdfFilstørrelse 560 kBChecksum SHA-512
52c27fc7ca7d4fbcd1bd7e39e36b8ab55072c4205bec6a758b8c2c33d77114dc0b6d4228578566bcb16f32aaef895cfd2da4ebe198af613426899c8f968532f4
Type fulltextMimetype application/pdf

Andre lenker

Forlagets fulltekstPubMed

Personposter BETA

Varasteh, ZohrehRosenström, UlrikaVelikyan, IrinaAltai, MohamedHonarvar, HadisRosestedt, MariaLindeberg, GunnarSörensen, JensLarhed, MatsTolmachev, VladimirOrlova, Anna

Søk i DiVA

Av forfatter/redaktør
Varasteh, ZohrehRosenström, UlrikaVelikyan, IrinaAltai, MohamedHonarvar, HadisRosestedt, MariaLindeberg, GunnarSörensen, JensLarhed, MatsTolmachev, VladimirOrlova, Anna
Av organisasjonen
I samme tidsskrift
Molecules

Søk utenfor DiVA

GoogleGoogle Scholar
Totalt: 491 nedlastinger
Antall nedlastinger er summen av alle nedlastinger av alle fulltekster. Det kan for eksempel være tidligere versjoner som er ikke lenger tilgjengelige

doi
pubmed
urn-nbn

Altmetric

doi
pubmed
urn-nbn
Totalt: 1106 treff
RefereraExporteraLink to record
Permanent link

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