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The Effect of Mini-...
The Effect of Mini-PEG-Based Spacer Length on Binding and Pharmacokinetic Properties of a Ga-68-Labeled NOTA-Conjugated Antagonistic Analog of Bombesin
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- Varasteh, Zohreh (author)
- Uppsala universitet,Plattformen för preklinisk PET
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- Rosenström, Ulrika (author)
- Uppsala universitet,Plattformen för preklinisk PET,Avdelningen för organisk farmaceutisk kemi
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- Velikyan, Irina (author)
- Uppsala universitet,Plattformen för preklinisk PET
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- Mitran, Bogdan (author)
- Uppsala universitet,Plattformen för preklinisk PET
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- Altai, Mohamed (author)
- Uppsala universitet,Enheten för biomedicinsk strålningsvetenskap
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- Honarvar, Hadis (author)
- Uppsala universitet,Enheten för biomedicinsk strålningsvetenskap
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- Rosestedt, Maria (author)
- Uppsala universitet,Plattformen för preklinisk PET
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- Lindeberg, Gunnar (author)
- Uppsala universitet,Avdelningen för organisk farmaceutisk kemi
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- Sörensen, Jens (author)
- Uppsala universitet,Klinisk fysiologi,Enheten för nuklearmedicin och PET
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- Larhed, Mats (author)
- Uppsala universitet,Plattformen för preklinisk PET,Avdelningen för organisk farmaceutisk kemi
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- Tolmachev, Vladimir (author)
- Uppsala universitet,Enheten för biomedicinsk strålningsvetenskap
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- Orlova, Anna (author)
- Uppsala universitet,Plattformen för preklinisk PET
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(creator_code:org_t)
- 2014-07-17
- 2014
- English.
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In: Molecules. - : MDPI AG. - 1431-5157 .- 1420-3049. ; 19:7, s. 10455-10472
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Abstract
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- 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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Radiologi och bildbehandling (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Radiology, Nuclear Medicine and Medical Imaging (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cancer and Oncology (hsv//eng)
Keyword
- bombesin analog
- PEG
- GRPR
- antagonist
- molecular imaging
- breast cancer
- prostate cancer
- BT-474
- PC-3 cells
Publication and Content Type
- ref (subject category)
- art (subject category)
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Varasteh, Zohreh
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Rosenström, Ulri ...
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Velikyan, Irina
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Mitran, Bogdan
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Altai, Mohamed
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Honarvar, Hadis
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Rosestedt, Maria
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Lindeberg, Gunna ...
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Sörensen, Jens
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Larhed, Mats
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Tolmachev, Vladi ...
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Orlova, Anna
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Molecules
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