Optimal composition and position of histidine-containing tags improves biodistribution of 99mTc-labeled DARPin G3

Anzhelika Vorobyeva, Alexey Schulga, Elena Konovalova, Rezan Güler, John Löfblom, Mattias Sandström, Javad Garousi, Vladimir Chernov, Olga Bragina, Anna Orlova, Vladimir Tolmachev, Sergey M. Deyev

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Radionuclide molecular imaging of HER2 expression in disseminated cancer enables stratification of patients for HER2-targeted therapies. DARPin G3, a small (14 kDa) engineered scaffold protein, is a promising probe for imaging of HER2. We hypothesized that position (C- or N-terminus) and composition (hexahistidine or (HE)3) of histidine-containing tags would influence the biodistribution of [99mTc]Tc(CO)3-labeled DARPin G3. To test the hypothesis, G3 variants containing tags at N-terminus (H6-G3 and (HE)3-G3) or at C-terminus (G3-H6 and G3-(HE)3) were labeled with [99mTc]Tc(CO)3. Labeling yield, label stability, specificity and affinity of the binding to HER2, biodistribution and tumor targeting properties of these variants were compared side-by-side. There was no substantial influence of position and composition of the tags on binding of [99mTc]Tc(CO)3-labeled variants to HER2. The specificity of HER2 targeting in vivo was confirmed. The tumor uptake in BALB/c nu/nu mice bearing SKOV3 xenografts was similar for all variants. On the opposite, there was a strong influence of the tags on uptake in normal tissues. The tumor-to-liver ratio for [99mTc]Tc(CO)3-(HE)3-G3 was three-fold higher compared to the hexahistidine-tag containing variants. Overall, [99mTc]Tc(CO)3-(HE)3-G3 variant provided the highest tumor-to-lung, tumor-to-liver, tumor-to-bone and tumor-to-muscle ratios, which should improve sensitivity of HER2 imaging in these common metastatic sites.

Original languageEnglish
Article number9405
JournalScientific Reports
Volume9
Issue number1
DOIs
Publication statusPublished - 1 Dec 2019

Fingerprint

His-His-His-His-His-His
Histidine
Carbon Monoxide
Neoplasms
Molecular Imaging
Liver
Heterografts
Radionuclide Imaging

ASJC Scopus subject areas

  • General

Cite this

Optimal composition and position of histidine-containing tags improves biodistribution of 99mTc-labeled DARPin G3. / Vorobyeva, Anzhelika; Schulga, Alexey; Konovalova, Elena; Güler, Rezan; Löfblom, John; Sandström, Mattias; Garousi, Javad; Chernov, Vladimir; Bragina, Olga; Orlova, Anna; Tolmachev, Vladimir; Deyev, Sergey M.

In: Scientific Reports, Vol. 9, No. 1, 9405, 01.12.2019.

Research output: Contribution to journalArticle

Vorobyeva, A, Schulga, A, Konovalova, E, Güler, R, Löfblom, J, Sandström, M, Garousi, J, Chernov, V, Bragina, O, Orlova, A, Tolmachev, V & Deyev, SM 2019, 'Optimal composition and position of histidine-containing tags improves biodistribution of 99mTc-labeled DARPin G3', Scientific Reports, vol. 9, no. 1, 9405. https://doi.org/10.1038/s41598-019-45795-8
Vorobyeva, Anzhelika ; Schulga, Alexey ; Konovalova, Elena ; Güler, Rezan ; Löfblom, John ; Sandström, Mattias ; Garousi, Javad ; Chernov, Vladimir ; Bragina, Olga ; Orlova, Anna ; Tolmachev, Vladimir ; Deyev, Sergey M. / Optimal composition and position of histidine-containing tags improves biodistribution of 99mTc-labeled DARPin G3. In: Scientific Reports. 2019 ; Vol. 9, No. 1.
@article{ac766bd9359040849e1f6d7a81a7e6a1,
title = "Optimal composition and position of histidine-containing tags improves biodistribution of 99mTc-labeled DARPin G3",
abstract = "Radionuclide molecular imaging of HER2 expression in disseminated cancer enables stratification of patients for HER2-targeted therapies. DARPin G3, a small (14 kDa) engineered scaffold protein, is a promising probe for imaging of HER2. We hypothesized that position (C- or N-terminus) and composition (hexahistidine or (HE)3) of histidine-containing tags would influence the biodistribution of [99mTc]Tc(CO)3-labeled DARPin G3. To test the hypothesis, G3 variants containing tags at N-terminus (H6-G3 and (HE)3-G3) or at C-terminus (G3-H6 and G3-(HE)3) were labeled with [99mTc]Tc(CO)3. Labeling yield, label stability, specificity and affinity of the binding to HER2, biodistribution and tumor targeting properties of these variants were compared side-by-side. There was no substantial influence of position and composition of the tags on binding of [99mTc]Tc(CO)3-labeled variants to HER2. The specificity of HER2 targeting in vivo was confirmed. The tumor uptake in BALB/c nu/nu mice bearing SKOV3 xenografts was similar for all variants. On the opposite, there was a strong influence of the tags on uptake in normal tissues. The tumor-to-liver ratio for [99mTc]Tc(CO)3-(HE)3-G3 was three-fold higher compared to the hexahistidine-tag containing variants. Overall, [99mTc]Tc(CO)3-(HE)3-G3 variant provided the highest tumor-to-lung, tumor-to-liver, tumor-to-bone and tumor-to-muscle ratios, which should improve sensitivity of HER2 imaging in these common metastatic sites.",
author = "Anzhelika Vorobyeva and Alexey Schulga and Elena Konovalova and Rezan G{\"u}ler and John L{\"o}fblom and Mattias Sandstr{\"o}m and Javad Garousi and Vladimir Chernov and Olga Bragina and Anna Orlova and Vladimir Tolmachev and Deyev, {Sergey M.}",
year = "2019",
month = "12",
day = "1",
doi = "10.1038/s41598-019-45795-8",
language = "English",
volume = "9",
journal = "Scientific Reports",
issn = "2045-2322",
publisher = "Nature Publishing Group",
number = "1",

}

TY - JOUR

T1 - Optimal composition and position of histidine-containing tags improves biodistribution of 99mTc-labeled DARPin G3

AU - Vorobyeva, Anzhelika

AU - Schulga, Alexey

AU - Konovalova, Elena

AU - Güler, Rezan

AU - Löfblom, John

AU - Sandström, Mattias

AU - Garousi, Javad

AU - Chernov, Vladimir

AU - Bragina, Olga

AU - Orlova, Anna

AU - Tolmachev, Vladimir

AU - Deyev, Sergey M.

PY - 2019/12/1

Y1 - 2019/12/1

N2 - Radionuclide molecular imaging of HER2 expression in disseminated cancer enables stratification of patients for HER2-targeted therapies. DARPin G3, a small (14 kDa) engineered scaffold protein, is a promising probe for imaging of HER2. We hypothesized that position (C- or N-terminus) and composition (hexahistidine or (HE)3) of histidine-containing tags would influence the biodistribution of [99mTc]Tc(CO)3-labeled DARPin G3. To test the hypothesis, G3 variants containing tags at N-terminus (H6-G3 and (HE)3-G3) or at C-terminus (G3-H6 and G3-(HE)3) were labeled with [99mTc]Tc(CO)3. Labeling yield, label stability, specificity and affinity of the binding to HER2, biodistribution and tumor targeting properties of these variants were compared side-by-side. There was no substantial influence of position and composition of the tags on binding of [99mTc]Tc(CO)3-labeled variants to HER2. The specificity of HER2 targeting in vivo was confirmed. The tumor uptake in BALB/c nu/nu mice bearing SKOV3 xenografts was similar for all variants. On the opposite, there was a strong influence of the tags on uptake in normal tissues. The tumor-to-liver ratio for [99mTc]Tc(CO)3-(HE)3-G3 was three-fold higher compared to the hexahistidine-tag containing variants. Overall, [99mTc]Tc(CO)3-(HE)3-G3 variant provided the highest tumor-to-lung, tumor-to-liver, tumor-to-bone and tumor-to-muscle ratios, which should improve sensitivity of HER2 imaging in these common metastatic sites.

AB - Radionuclide molecular imaging of HER2 expression in disseminated cancer enables stratification of patients for HER2-targeted therapies. DARPin G3, a small (14 kDa) engineered scaffold protein, is a promising probe for imaging of HER2. We hypothesized that position (C- or N-terminus) and composition (hexahistidine or (HE)3) of histidine-containing tags would influence the biodistribution of [99mTc]Tc(CO)3-labeled DARPin G3. To test the hypothesis, G3 variants containing tags at N-terminus (H6-G3 and (HE)3-G3) or at C-terminus (G3-H6 and G3-(HE)3) were labeled with [99mTc]Tc(CO)3. Labeling yield, label stability, specificity and affinity of the binding to HER2, biodistribution and tumor targeting properties of these variants were compared side-by-side. There was no substantial influence of position and composition of the tags on binding of [99mTc]Tc(CO)3-labeled variants to HER2. The specificity of HER2 targeting in vivo was confirmed. The tumor uptake in BALB/c nu/nu mice bearing SKOV3 xenografts was similar for all variants. On the opposite, there was a strong influence of the tags on uptake in normal tissues. The tumor-to-liver ratio for [99mTc]Tc(CO)3-(HE)3-G3 was three-fold higher compared to the hexahistidine-tag containing variants. Overall, [99mTc]Tc(CO)3-(HE)3-G3 variant provided the highest tumor-to-lung, tumor-to-liver, tumor-to-bone and tumor-to-muscle ratios, which should improve sensitivity of HER2 imaging in these common metastatic sites.

UR - http://www.scopus.com/inward/record.url?scp=85068108800&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85068108800&partnerID=8YFLogxK

U2 - 10.1038/s41598-019-45795-8

DO - 10.1038/s41598-019-45795-8

M3 - Article

VL - 9

JO - Scientific Reports

JF - Scientific Reports

SN - 2045-2322

IS - 1

M1 - 9405

ER -