68Ga-labeled phage-display selected peptides as tracers for positron emission tomography imaging of Staphylococcus aureus biofilm-associated infections: selection, radiolabelling and preliminary biological evaluation

Karin Michaelsen Nielsen; Majbritt Hauge Kyneb; Aage Kristian Olsen Alstrup; Jakob J. Jensen; Dirk Bender; Henrik Carl Schønheyder; Pia  Afzelius; Ole Lerberg Nielsen; Svend B. Jensen

doi:10.1016/j.nucmedbio.2016.07.002

⁶⁸Ga-labeled phage-display selected peptides as tracers for positron emission tomography imaging of Staphylococcus aureus biofilm-associated infections: selection, radiolabelling and preliminary biological evaluation

Karin Michaelsen Nielsen, Majbritt Hauge Kyneb, Aage Kristian Olsen Alstrup, Jakob J. Jensen, Dirk Bender, Henrik Carl Schønheyder, Pia Afzelius, Ole Lerberg Nielsen, Svend B. Jensen

7 Citations (Scopus)

Abstract

Introduction Staphylococcus aureus is a major cause of skin and deep-sited infections, often associated with the formation of biofilms. Early diagnosis and initiated therapy is essential to prevent disease progression and to reduce complications that can be serious. Imaging techniques are helpful combining anatomical with functional data in order to describe and characterize site, extent and activity of the disease. The purpose of the study was to identify and ⁶⁸Ga-label peptides with affinity for S. aureus biofilm and evaluate their potential as bacteria-specific positron emission tomography (PET) imaging agents. Methods Phage-displayed dodecapeptides were selected using an in vitro grown S. aureus biofilm as target. One cyclic (A8) and two linear (A9, A11) dodecapeptides were custom synthesized with 1,4,7,10-tetraazacyclododecane-N,N′,N″,N‴-tetraacetic acid (DOTA) conjugated via a lysine linker (K), and for A11 also a glycine–serine–glycine spacer (GSG). The ⁶⁸Ga-labeling of A8-K-DOTA, A9-K-DOTA, and A11-GSGK-DOTA were optimized and in vitro bacterial binding was evaluated for ⁶⁸Ga-A9-K-DOTA and ⁶⁸Ga-A11-GSGK-DOTA. Stability of ⁶⁸Ga-A9-K-DOTA was studied in vitro in human serum, while the in vivo plasma stability was analyzed in mice and pigs. Additionally, the whole-body distribution kinetics of ⁶⁸Ga-A9-K-DOTA was measured in vivo by PET imaging of pigs and ex vivo in excised mice tissues. Results The ⁶⁸Ga-A9-K-DOTA and ⁶⁸Ga-A11-GSGK-DOTA remained stable in product formulation, whereas ⁶⁸Ga-A8-K-DOTA was unstable. The S. aureus binding of ⁶⁸Ga-A11-GSGK-DOTA and ⁶⁸Ga-A9-K-DOTA was observed in vitro, though blocking of the binding was not possible by excess of cold peptide. The ⁶⁸Ga-A9-K-DOTA was degraded slowly in vitro, while the combined in vivo evaluation in pigs and mice showed a rapid blood clearance and renal excretion of the ⁶⁸Ga-A9-K-DOTA. Conclusion The preliminary in vitro and in vivo studies of the phage-display S. aureus biofilm-selected ⁶⁸Ga-A9-K-DOTA showed desirable features for a novel bacteria-specific imaging agent, despite of relative fast blood degradation in vivo.

Original language	English
Journal	Nuclear Medicine and Biology
Volume	43
Issue number	10
Pages (from-to)	593-605
Number of pages	13
ISSN	0969-8051
DOIs	https://doi.org/10.1016/j.nucmedbio.2016.07.002
Publication status	Published - 1 Oct 2016

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Nielsen, K. M., Kyneb, M. H., Alstrup, A. K. O., Jensen, J. J., Bender, D., Schønheyder, H. C., Afzelius, P., Nielsen, O. L., & Jensen, S. B. (2016). ⁶⁸Ga-labeled phage-display selected peptides as tracers for positron emission tomography imaging of Staphylococcus aureus biofilm-associated infections: selection, radiolabelling and preliminary biological evaluation. Nuclear Medicine and Biology, 43(10), 593-605. https://doi.org/10.1016/j.nucmedbio.2016.07.002

⁶⁸Ga-labeled phage-display selected peptides as tracers for positron emission tomography imaging of Staphylococcus aureus biofilm-associated infections: selection, radiolabelling and preliminary biological evaluation. / Nielsen, Karin Michaelsen; Kyneb, Majbritt Hauge; Alstrup, Aage Kristian Olsen et al.
In: Nuclear Medicine and Biology, Vol. 43, No. 10, 01.10.2016, p. 593-605.

Research output: Contribution to journal › Journal article › Research › peer-review

Nielsen, KM, Kyneb, MH, Alstrup, AKO, Jensen, JJ, Bender, D, Schønheyder, HC, Afzelius, P, Nielsen, OL & Jensen, SB 2016, '⁶⁸Ga-labeled phage-display selected peptides as tracers for positron emission tomography imaging of Staphylococcus aureus biofilm-associated infections: selection, radiolabelling and preliminary biological evaluation', Nuclear Medicine and Biology, vol. 43, no. 10, pp. 593-605. https://doi.org/10.1016/j.nucmedbio.2016.07.002

Nielsen KM, Kyneb MH, Alstrup AKO, Jensen JJ, Bender D, Schønheyder HC et al. ⁶⁸Ga-labeled phage-display selected peptides as tracers for positron emission tomography imaging of Staphylococcus aureus biofilm-associated infections: selection, radiolabelling and preliminary biological evaluation. Nuclear Medicine and Biology. 2016 Oct 1;43(10):593-605. doi: 10.1016/j.nucmedbio.2016.07.002

Nielsen, Karin Michaelsen ; Kyneb, Majbritt Hauge ; Alstrup, Aage Kristian Olsen et al. / ⁶⁸Ga-labeled phage-display selected peptides as tracers for positron emission tomography imaging of Staphylococcus aureus biofilm-associated infections : selection, radiolabelling and preliminary biological evaluation. In: Nuclear Medicine and Biology. 2016 ; Vol. 43, No. 10. pp. 593-605.

@article{de229bc290e243d89b5d273e3da78592,

title = "68Ga-labeled phage-display selected peptides as tracers for positron emission tomography imaging of Staphylococcus aureus biofilm-associated infections: selection, radiolabelling and preliminary biological evaluation",

abstract = "Introduction Staphylococcus aureus is a major cause of skin and deep-sited infections, often associated with the formation of biofilms. Early diagnosis and initiated therapy is essential to prevent disease progression and to reduce complications that can be serious. Imaging techniques are helpful combining anatomical with functional data in order to describe and characterize site, extent and activity of the disease. The purpose of the study was to identify and 68Ga-label peptides with affinity for S. aureus biofilm and evaluate their potential as bacteria-specific positron emission tomography (PET) imaging agents. Methods Phage-displayed dodecapeptides were selected using an in vitro grown S. aureus biofilm as target. One cyclic (A8) and two linear (A9, A11) dodecapeptides were custom synthesized with 1,4,7,10-tetraazacyclododecane-N,N′,N″,N‴-tetraacetic acid (DOTA) conjugated via a lysine linker (K), and for A11 also a glycine–serine–glycine spacer (GSG). The 68Ga-labeling of A8-K-DOTA, A9-K-DOTA, and A11-GSGK-DOTA were optimized and in vitro bacterial binding was evaluated for 68Ga-A9-K-DOTA and 68Ga-A11-GSGK-DOTA. Stability of 68Ga-A9-K-DOTA was studied in vitro in human serum, while the in vivo plasma stability was analyzed in mice and pigs. Additionally, the whole-body distribution kinetics of 68Ga-A9-K-DOTA was measured in vivo by PET imaging of pigs and ex vivo in excised mice tissues. Results The 68Ga-A9-K-DOTA and 68Ga-A11-GSGK-DOTA remained stable in product formulation, whereas 68Ga-A8-K-DOTA was unstable. The S. aureus binding of 68Ga-A11-GSGK-DOTA and 68Ga-A9-K-DOTA was observed in vitro, though blocking of the binding was not possible by excess of cold peptide. The 68Ga-A9-K-DOTA was degraded slowly in vitro, while the combined in vivo evaluation in pigs and mice showed a rapid blood clearance and renal excretion of the 68Ga-A9-K-DOTA. Conclusion The preliminary in vitro and in vivo studies of the phage-display S. aureus biofilm-selected 68Ga-A9-K-DOTA showed desirable features for a novel bacteria-specific imaging agent, despite of relative fast blood degradation in vivo.",

author = "Nielsen, {Karin Michaelsen} and Kyneb, {Majbritt Hauge} and Alstrup, {Aage Kristian Olsen} and Jensen, {Jakob J.} and Dirk Bender and Sch{\o}nheyder, {Henrik Carl} and Pia Afzelius and Nielsen, {Ole Lerberg} and Jensen, {Svend B.}",

year = "2016",

month = oct,

day = "1",

doi = "10.1016/j.nucmedbio.2016.07.002",

language = "English",

volume = "43",

pages = "593--605",

journal = "Nuclear Medicine and Biology",

issn = "0969-8051",

publisher = "Elsevier",

number = "10",

}

TY - JOUR

T1 - 68Ga-labeled phage-display selected peptides as tracers for positron emission tomography imaging of Staphylococcus aureus biofilm-associated infections

T2 - selection, radiolabelling and preliminary biological evaluation

AU - Nielsen, Karin Michaelsen

AU - Kyneb, Majbritt Hauge

AU - Alstrup, Aage Kristian Olsen

AU - Jensen, Jakob J.

AU - Bender, Dirk

AU - Schønheyder, Henrik Carl

AU - Afzelius, Pia

AU - Nielsen, Ole Lerberg

AU - Jensen, Svend B.

PY - 2016/10/1

Y1 - 2016/10/1

N2 - Introduction Staphylococcus aureus is a major cause of skin and deep-sited infections, often associated with the formation of biofilms. Early diagnosis and initiated therapy is essential to prevent disease progression and to reduce complications that can be serious. Imaging techniques are helpful combining anatomical with functional data in order to describe and characterize site, extent and activity of the disease. The purpose of the study was to identify and 68Ga-label peptides with affinity for S. aureus biofilm and evaluate their potential as bacteria-specific positron emission tomography (PET) imaging agents. Methods Phage-displayed dodecapeptides were selected using an in vitro grown S. aureus biofilm as target. One cyclic (A8) and two linear (A9, A11) dodecapeptides were custom synthesized with 1,4,7,10-tetraazacyclododecane-N,N′,N″,N‴-tetraacetic acid (DOTA) conjugated via a lysine linker (K), and for A11 also a glycine–serine–glycine spacer (GSG). The 68Ga-labeling of A8-K-DOTA, A9-K-DOTA, and A11-GSGK-DOTA were optimized and in vitro bacterial binding was evaluated for 68Ga-A9-K-DOTA and 68Ga-A11-GSGK-DOTA. Stability of 68Ga-A9-K-DOTA was studied in vitro in human serum, while the in vivo plasma stability was analyzed in mice and pigs. Additionally, the whole-body distribution kinetics of 68Ga-A9-K-DOTA was measured in vivo by PET imaging of pigs and ex vivo in excised mice tissues. Results The 68Ga-A9-K-DOTA and 68Ga-A11-GSGK-DOTA remained stable in product formulation, whereas 68Ga-A8-K-DOTA was unstable. The S. aureus binding of 68Ga-A11-GSGK-DOTA and 68Ga-A9-K-DOTA was observed in vitro, though blocking of the binding was not possible by excess of cold peptide. The 68Ga-A9-K-DOTA was degraded slowly in vitro, while the combined in vivo evaluation in pigs and mice showed a rapid blood clearance and renal excretion of the 68Ga-A9-K-DOTA. Conclusion The preliminary in vitro and in vivo studies of the phage-display S. aureus biofilm-selected 68Ga-A9-K-DOTA showed desirable features for a novel bacteria-specific imaging agent, despite of relative fast blood degradation in vivo.

AB - Introduction Staphylococcus aureus is a major cause of skin and deep-sited infections, often associated with the formation of biofilms. Early diagnosis and initiated therapy is essential to prevent disease progression and to reduce complications that can be serious. Imaging techniques are helpful combining anatomical with functional data in order to describe and characterize site, extent and activity of the disease. The purpose of the study was to identify and 68Ga-label peptides with affinity for S. aureus biofilm and evaluate their potential as bacteria-specific positron emission tomography (PET) imaging agents. Methods Phage-displayed dodecapeptides were selected using an in vitro grown S. aureus biofilm as target. One cyclic (A8) and two linear (A9, A11) dodecapeptides were custom synthesized with 1,4,7,10-tetraazacyclododecane-N,N′,N″,N‴-tetraacetic acid (DOTA) conjugated via a lysine linker (K), and for A11 also a glycine–serine–glycine spacer (GSG). The 68Ga-labeling of A8-K-DOTA, A9-K-DOTA, and A11-GSGK-DOTA were optimized and in vitro bacterial binding was evaluated for 68Ga-A9-K-DOTA and 68Ga-A11-GSGK-DOTA. Stability of 68Ga-A9-K-DOTA was studied in vitro in human serum, while the in vivo plasma stability was analyzed in mice and pigs. Additionally, the whole-body distribution kinetics of 68Ga-A9-K-DOTA was measured in vivo by PET imaging of pigs and ex vivo in excised mice tissues. Results The 68Ga-A9-K-DOTA and 68Ga-A11-GSGK-DOTA remained stable in product formulation, whereas 68Ga-A8-K-DOTA was unstable. The S. aureus binding of 68Ga-A11-GSGK-DOTA and 68Ga-A9-K-DOTA was observed in vitro, though blocking of the binding was not possible by excess of cold peptide. The 68Ga-A9-K-DOTA was degraded slowly in vitro, while the combined in vivo evaluation in pigs and mice showed a rapid blood clearance and renal excretion of the 68Ga-A9-K-DOTA. Conclusion The preliminary in vitro and in vivo studies of the phage-display S. aureus biofilm-selected 68Ga-A9-K-DOTA showed desirable features for a novel bacteria-specific imaging agent, despite of relative fast blood degradation in vivo.

U2 - 10.1016/j.nucmedbio.2016.07.002

DO - 10.1016/j.nucmedbio.2016.07.002

M3 - Journal article

C2 - 27474962

SN - 0969-8051

VL - 43

SP - 593

EP - 605

JO - Nuclear Medicine and Biology

JF - Nuclear Medicine and Biology

IS - 10

ER -