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Title: The effect of bi-terminal PEGylation of an integrin  α vβ 6-targeted 18F peptide on pharmacokinetics and tumor uptake

Abstract

Radiotracers based on the peptide A20FMDV2 selectively target the cell surface receptor integrin α vβ 6. This integrin has been identified as a prognostic indicator correlating with the severity of disease for several challenging malignancies. In previous studies of A20FMDV2 peptides labeled with 4- 18F-fluorobenzoic acid ( 18F-FBA), we have shown that the introduction of poly(ethylene glycol) (PEG) improves pharmacokinetics, including increased uptake in α vβ 6-expressing tumors. The present study evaluated the effect of site-specific C-terminal or dual (N- and C-terminal) PEGylation, yielding 18F-FBA-A20FMDV2-PEG 28 (4) and 18F-FBA-PEG 28-A20FMDV2-PEG 28 (5), on α vβ 6-targeted tumor uptake and pharmacokinetics. The results are compared with 18F-FBA–labeled A20FMDV2 radiotracers (1–3) bearing either no PEG or different PEG units at the N terminus. The radiotracers were prepared and radiolabeled on solid phase. Using 3 cell lines, DX3puroβ6 (α vβ 6+), DX3puro (α vβ 6–), and BxPC-3 (α vβ 6+), we evaluated the radiotracers in vitro (serum stability; cell binding and internalization) and in vivo in mouse models bearing paired DX3puroβ6–DX3puro and, for 5, BxPC-3 xenografts. Here, the size and location of the PEG units significantly affected α vβ 6 targeting and pharmacokinetics. Although the C-terminally PEGylated 4 showed some improvements over themore » un-PEGylated 18F-FBA-A20FMDV2 (1), it was the bi-terminally PEGylated 5 that displayed the more favorable combination of high α vβ 6 affinity, selectivity, and pharmacokinetic profile. In vitro, 5 bound to α vβ 6-expressing DX3puroβ6 and BxPC-3 cells with 60.5% ± 3.3% and 48.8% ± 8.3%, respectively, with a significant fraction of internalization (37.2% ± 4.0% and 37.6% ± 4.1% of total radioactivity, respectively). By comparison, in the DX3puro control 5 showed only 3.0% ± 0.5% binding and 0.9% ± 0.2% internalization. In vivo, 5 maintained high, α vβ 6-directed binding in the paired DX3puroβ6–DX3puro model (1 h: DX3puroβ6, 2.3 ± 0.2 percentage injected dose per gram [%ID/g]; DX3puroβ6/DX3puro ratio, 6.5:1; 4 h: 10.7:1). In the pancreatic BxPC-3 model, uptake was 4.7 ± 0.9 %ID/g (1 h) despite small tumor sizes (20–80 mg). In conclusion, the bi-PEGylated radiotracer 5 showed a greatly improved pharmacokinetic profile, beyond what was predicted from individual N- or C-terminal PEGylation. It appears that the 2 PEG units acted synergistically to result in an improved metabolic profile including high α vβ 6+ tumor uptake and retention.« less

Authors:
 [1];  [2];  [2];  [3];  [1]
  1. Univ. of California Davis, Sacramento, CA (United States); Univ. of California, Davis, CA (United States)
  2. Univ. of California, Davis, CA (United States)
  3. Univ. of California Davis, Sacramento, CA (United States)
Publication Date:
Research Org.:
Univ. of California, Davis, CA (United States)
Sponsoring Org.:
USDOE Office of Science (SC)
OSTI Identifier:
1345593
Grant/Contract Number:  
SC0002061
Resource Type:
Journal Article: Accepted Manuscript
Journal Name:
Journal of Nuclear Medicine
Additional Journal Information:
Journal Volume: 56; Journal Issue: 5; Journal ID: ISSN 0161-5505
Publisher:
Society of Nuclear Medicine and Molecular Imaging
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES; integrin αvβ6; positron emission tomography; peptide; PEGylation; metabolism

Citation Formats

Hausner, Sven H., Bauer, Nadine, Hu, Lina Y., Knight, Leah M., and Sutcliffe, Julie L. The effect of bi-terminal PEGylation of an integrin  αvβ6-targeted 18F peptide on pharmacokinetics and tumor uptake. United States: N. p., 2015. Web. doi:10.2967/jnumed.114.150680.
Hausner, Sven H., Bauer, Nadine, Hu, Lina Y., Knight, Leah M., & Sutcliffe, Julie L. The effect of bi-terminal PEGylation of an integrin  αvβ6-targeted 18F peptide on pharmacokinetics and tumor uptake. United States. doi:10.2967/jnumed.114.150680.
Hausner, Sven H., Bauer, Nadine, Hu, Lina Y., Knight, Leah M., and Sutcliffe, Julie L. Thu . "The effect of bi-terminal PEGylation of an integrin  αvβ6-targeted 18F peptide on pharmacokinetics and tumor uptake". United States. doi:10.2967/jnumed.114.150680. https://www.osti.gov/servlets/purl/1345593.
@article{osti_1345593,
title = {The effect of bi-terminal PEGylation of an integrin  αvβ6-targeted 18F peptide on pharmacokinetics and tumor uptake},
author = {Hausner, Sven H. and Bauer, Nadine and Hu, Lina Y. and Knight, Leah M. and Sutcliffe, Julie L.},
abstractNote = {Radiotracers based on the peptide A20FMDV2 selectively target the cell surface receptor integrin αvβ6. This integrin has been identified as a prognostic indicator correlating with the severity of disease for several challenging malignancies. In previous studies of A20FMDV2 peptides labeled with 4-18F-fluorobenzoic acid (18F-FBA), we have shown that the introduction of poly(ethylene glycol) (PEG) improves pharmacokinetics, including increased uptake in αvβ6-expressing tumors. The present study evaluated the effect of site-specific C-terminal or dual (N- and C-terminal) PEGylation, yielding 18F-FBA-A20FMDV2-PEG28 (4) and 18F-FBA-PEG28-A20FMDV2-PEG28 (5), on αvβ6-targeted tumor uptake and pharmacokinetics. The results are compared with 18F-FBA–labeled A20FMDV2 radiotracers (1–3) bearing either no PEG or different PEG units at the N terminus. The radiotracers were prepared and radiolabeled on solid phase. Using 3 cell lines, DX3puroβ6 (αvβ6+), DX3puro (αvβ6–), and BxPC-3 (αvβ6+), we evaluated the radiotracers in vitro (serum stability; cell binding and internalization) and in vivo in mouse models bearing paired DX3puroβ6–DX3puro and, for 5, BxPC-3 xenografts. Here, the size and location of the PEG units significantly affected αvβ6 targeting and pharmacokinetics. Although the C-terminally PEGylated 4 showed some improvements over the un-PEGylated 18F-FBA-A20FMDV2 (1), it was the bi-terminally PEGylated 5 that displayed the more favorable combination of high αvβ6 affinity, selectivity, and pharmacokinetic profile. In vitro, 5 bound to αvβ6-expressing DX3puroβ6 and BxPC-3 cells with 60.5% ± 3.3% and 48.8% ± 8.3%, respectively, with a significant fraction of internalization (37.2% ± 4.0% and 37.6% ± 4.1% of total radioactivity, respectively). By comparison, in the DX3puro control 5 showed only 3.0% ± 0.5% binding and 0.9% ± 0.2% internalization. In vivo, 5 maintained high, αvβ6-directed binding in the paired DX3puroβ6–DX3puro model (1 h: DX3puroβ6, 2.3 ± 0.2 percentage injected dose per gram [%ID/g]; DX3puroβ6/DX3puro ratio, 6.5:1; 4 h: 10.7:1). In the pancreatic BxPC-3 model, uptake was 4.7 ± 0.9 %ID/g (1 h) despite small tumor sizes (20–80 mg). In conclusion, the bi-PEGylated radiotracer 5 showed a greatly improved pharmacokinetic profile, beyond what was predicted from individual N- or C-terminal PEGylation. It appears that the 2 PEG units acted synergistically to result in an improved metabolic profile including high αvβ6+ tumor uptake and retention.},
doi = {10.2967/jnumed.114.150680},
journal = {Journal of Nuclear Medicine},
number = 5,
volume = 56,
place = {United States},
year = {Thu Mar 26 00:00:00 EDT 2015},
month = {Thu Mar 26 00:00:00 EDT 2015}
}

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