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(68)Ga-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 M; Kyneb, Majbritt H; Alstrup, Aage K O; Jensen, Jakob J; Bender, Dirk; Schønheyder, Henrik C; Afzelius, Pia; Nielsen, Ole L; Jensen, Svend B.
Afiliação
  • Nielsen KM; Department of Nuclear Medicine, Aalborg University Hospital, DK-9000 Aalborg, Denmark; Department of Veterinary Disease Biology, Faculty of Health and Medical Sciences, University of Copenhagen, DK-1870 Copenhagen, Denmark. Electronic address: karin.michaelsen.nielsen@regionh.dk.
  • Kyneb MH; Section for Medical Biotechnology, Danish Technological Institute, DK-8000 Aarhus, Denmark.
  • Alstrup AK; Department of Nuclear Medicine and PET-centre, Aarhus University Hospital, DK-8000 Aarhus, Denmark.
  • Jensen JJ; Department of Nuclear Medicine, Aalborg University Hospital, DK-9000 Aalborg, Denmark; Section for Medical Biotechnology, Danish Technological Institute, DK-8000 Aarhus, Denmark.
  • Bender D; Department of Nuclear Medicine and PET-centre, Aarhus University Hospital, DK-8000 Aarhus, Denmark.
  • Schønheyder HC; Department of Clinical Microbiology, Aalborg University Hospital, DK-9000 Aalborg, Denmark; Department of Clinical Medicine, Aalborg University, DK-9000 Aalborg, Denmark.
  • Afzelius P; Department of Diagnostic Imaging, Section of Clinical Physiology and Nuclear Medicine, Copenhagen University Hospital, North Zealand, DK-3400 Hillerød, Denmark.
  • Nielsen OL; Department of Veterinary Disease Biology, Faculty of Health and Medical Sciences, University of Copenhagen, DK-1870 Copenhagen, Denmark.
  • Jensen SB; Department of Nuclear Medicine, Aalborg University Hospital, DK-9000 Aalborg, Denmark; Department of Chemistry and Biochemistry, Aalborg University, DK-9000 Aalborg, Denmark.
Nucl Med Biol ; 43(10): 593-605, 2016 10.
Article em En | MEDLINE | ID: mdl-27474962
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 (68)Ga-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 (68)Ga-labeling of A8-K-DOTA, A9-K-DOTA, and A11-GSGK-DOTA were optimized and in vitro bacterial binding was evaluated for (68)Ga-A9-K-DOTA and (68)Ga-A11-GSGK-DOTA. Stability of (68)Ga-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 (68)Ga-A9-K-DOTA was measured in vivo by PET imaging of pigs and ex vivo in excised mice tissues.

RESULTS:

The (68)Ga-A9-K-DOTA and (68)Ga-A11-GSGK-DOTA remained stable in product formulation, whereas (68)Ga-A8-K-DOTA was unstable. The S. aureus binding of (68)Ga-A11-GSGK-DOTA and (68)Ga-A9-K-DOTA was observed in vitro, though blocking of the binding was not possible by excess of cold peptide. The (68)Ga-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 (68)Ga-A9-K-DOTA.

CONCLUSION:

The preliminary in vitro and in vivo studies of the phage-display S. aureus biofilm-selected (68)Ga-A9-K-DOTA showed desirable features for a novel bacteria-specific imaging agent, despite of relative fast blood degradation in vivo.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Oligopeptídeos / Infecções Estafilocócicas / Staphylococcus aureus / Biofilmes / Biblioteca de Peptídeos / Tomografia por Emissão de Pósitrons / Radioisótopos de Gálio Idioma: En Ano de publicação: 2016 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Oligopeptídeos / Infecções Estafilocócicas / Staphylococcus aureus / Biofilmes / Biblioteca de Peptídeos / Tomografia por Emissão de Pósitrons / Radioisótopos de Gálio Idioma: En Ano de publicação: 2016 Tipo de documento: Article