Incorporation of a Triglutamyl Spacer Improves the Biodistribution of Synthetic Affibody Molecules Radiofluorinated at the N-Terminus via Oxime Formation with F-18-4-Fluorobenzaldehyde

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Incorporation of a Triglutamyl Spacer Improves the Biodistribution of Synthetic Affibody Molecules Radiofluorinated at the N-Terminus via Oxime Formation with F-18-4-Fluorobenzaldehyde

Rosik, Daniel (author): KTH,Proteinteknologi

Thibblin, Alf (author): Uppsala universitet,Plattformen för preklinisk PET

Antoni, Gunnar (author): Uppsala universitet,Plattformen för preklinisk PET,Enheten för onkologi

Orlova, Anna (author): Uppsala universitet,Plattformen för preklinisk PET

Eriksson Karlström, Amelie (author): KTH,Proteinteknologi

Tolmachev, Vladimir (author): Uppsala universitet,Enheten för biomedicinsk strålningsvetenskap,Tolmachev

Honarvar, Hadis (author): Uppsala universitet,Enheten för biomedicinsk strålningsvetenskap,Tolmachev

Strand, Joanna (author): Uppsala universitet,Enheten för biomedicinsk strålningsvetenskap,Tolmachev

Selvaraju, Ram Kumar (author): Uppsala universitet,Plattformen för preklinisk PET

Altai, Mohamed (author): Uppsala universitet,Enheten för biomedicinsk strålningsvetenskap,Tolmachev

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2013-12-27
2014
English.
In: Bioconjugate chemistry. - : American Chemical Society (ACS). - 1043-1802 .- 1520-4812. ; 25:1, s. 82-92

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Journal article (peer-reviewed)

Abstract Subject headings

Affibody molecules are a class of affinity agents for molecular imaging based on a non-immunoglobulin protein scaffold. Previous studies have demonstrated high contrast for in vivo imaging of cancer-associated molecular abnormalities using Affibody molecules. Using the radionuclide F-18 for labeling and PET as the imaging modality, the sensitivity of molecular imaging using Affibody molecules can be further increased. The use of oxime formation between an aminooxy-functionalized peptide and F-18-fluorobenzaldehyde (F-18-FBA) is a promising way of radiolabeling of targeting peptides. However, previous studies demonstrated that application of this method to Affibody molecules is associated with high liver uptake. We hypothesized that incorporation of a triglutamyl spacer between the aminooxy moiety and the N-terminus of a synthetic Affibody molecule would decrease the hepatic uptake of the F-18-N-(4-fluorobenzylidine)oxime) (F-18-FBO)-labeled tracer. To verify this, we have produced two variants of the HER2-targeting Z(HER2:342) Affibody molecule by peptide synthesis: OA-PEP4313, where aminooxyacetic acid was conjugated directly to the N-terminal alanine, and OA-E-3-PEP4313, where a triglutamyl spacer was introduced between the aminooxy moiety and the N-terminus. We have found that the use of the spacer is associated with a minor decrease of affinity, from K-D = 49 pM to K-D = 180 pM. Radiolabeled F-18-FBO-E-3-PEP4313 demonstrated specific binding to HER2-expressing ovarian carcinoma SKOV-3 cells and slow internalization. Biodistribution studies in mice demonstrated that the use of a triglutamyl linker decreased uptake of radioactivity in liver 2.7-fold at 2 h after injection. Interestingly, radioactivity uptake in kidneys was also reduced (2.4-fold). Experiments in BALB/C nu/nu mice bearing SKOV-3 xenografts demonstrated HER2-specific uptake of F-18-FBO-E-3-PEP4313 in tumors. At 2 h pi, the tumor uptake (20 +/- 2% ID/g) exceeded uptake in liver 5-fold and uptake in kidneys 3.6-fold. The tumor-to-blood ratio was 21 +/- 3. The microPET/CT imaging experiment confirmed the biodistribution data. In conclusion, the use of a triglutamyl spacer is a convenient way to improve the biodistribution profile of Affibody molecules labeled at the N-terminus using F-18-FBA. It provides a tracer capable of producing high-contrast images of HER2-expressing tumors.

Subject headings

TEKNIK OCH TEKNOLOGIER -- Medicinteknik -- Medicinsk laboratorie- och mätteknik (hsv//swe)
ENGINEERING AND TECHNOLOGY -- Medical Engineering -- Medical Laboratory and Measurements Technologies (hsv//eng)
MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper (hsv//swe)
MEDICAL AND HEALTH SCIENCES -- Basic Medicine (hsv//eng)

Keyword

Positron-Emission-Tomography
In-Vivo
Anti-Her2 Affibody
Labeling Methods
Her2 Expression
Immuno-Pet
Peptides
Affinity
Proteins
Receptor

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By the author/editor: Rosik, Daniel; Thibblin, Alf; Antoni, Gunnar; Orlova, Anna; Eriksson Karlstr ...; Tolmachev, Vladi ...; show more...; Honarvar, Hadis; Strand, Joanna; Selvaraju, Ram K ...; Altai, Mohamed; show less...

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ENGINEERING AND TECHNOLOGY: ENGINEERING AND ...; and Medical Engineer ...; and Medical Laborato ...

MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Basic Medicine

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By the university: Royal Institute of Technology; Uppsala University

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