Biological characterization of novel nitroimidazole-peptide conjugates in vitro and in vivo.
Recently, we reported on the design of a multimodal peptide conjugate useful as delivery platform for targeting hypoxic cells. A nitroimidazole (2-(2-nitroimidazol-1-yl)acetic acid, NIA) moiety, which is selectively entrapped in hypoxic cells, was coupled to a cell-penetrating peptide serving as the transporter. Furthermore, attachment of a bifunctional linker allowed the introduction of a diagnostic or therapeutic radiometal. However, although selective tumor accumulation could be detected in vivo, a fast renal clearance of the compound was observed. The present study aims to improve the system by using the more proteolytically stable all-d version of the peptide carrier (DsC18), by attaching two NIA moieties instead of one (DsC18(NIA)2) to enhance the tumor uptake, and by incorporating the bifunctional chelator NODAGA instead of DOTA (NODAGA-DsC18(NIA)2) to optimize labeling chemistry. First, we characterized in vitro the novel all-d peptide compared with its parent l-version. Then, in order to investigate and compare the pharmacological profiles of the peptides, these were radiolabeled with64CuIIand68GaIII, and the biodistribution and kinetics were evaluated in vivo. Our results show the versatility of the d-peptide as cell-penetrating peptide and transporter. However, attaching two NIA groups modified the system in such a way that no selective tumor uptake could be observed compared with the peptide without NIA moieties. Still, this work highlights new pharmacokinetic data on the biodistribution of such compounds in vivo. Copyright © 2017 European Peptide Society and John Wiley & Sons, Ltd.
Helmholtz-Zentrum Dresden-Rossendorf, Institut für Radiopharmazeutische Krebsforschung, PF 510119, D-01314, Dresden, Germany.
Ralf
R
Bergmann
Experimental Surgery, Campus Virchow, Charité Universitätsmedizin Berlin, Augustenburger Platz 1, D-13353, Berlin, Germany.
Katrin
K
Splith
Helmholtz-Zentrum Dresden-Rossendorf, Institut für Radiopharmazeutische Krebsforschung, PF 510119, D-01314, Dresden, Germany.|Fakultät Mathematik und Naturwissenschaften, Fachrichtung Chemie und Lebensmittelchemie, Technische Universität Dresden, D-01062, Dresden, Germany.
Jens
http://orcid.org/0000-0002-1610-1493
J
Pietzsch
Helmholtz-Zentrum Dresden-Rossendorf, Institut für Radiopharmazeutische Krebsforschung, PF 510119, D-01314, Dresden, Germany.|Tumorimmunology, Technische Universität Dresden, Fetscherstr. 74, D-01307, Dresden, Germany.|Nationales Zentrum für Tumorerkrankungen, Technische Universität, Fetscherstr. 74, D-01307, Dresden, Germany.|Universitäts Krebs Centrum Dresden, Dresden, Germany.
Michael
M
Bachmann
Department für Chemie, Institut für Biochemie, Mathematisch-Naturwissenschaftliche Fakultät, Universität zu Köln, Zülpicher Str. 47a, D-50674, Köln, Germany.
Ines
http://orcid.org/0000-0001-6450-3991
I
Neundorf
D057846:Cell-Penetrating Peptides / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D061986:MCF-7 Cells; D009593:Nitroimidazoles / Q000737:chemistry* / Q000378:metabolism; D010455:Peptides / Q000737:chemistry* / Q000378:metabolism; D049268:Positron-Emission Tomography
D057846:Cell-Penetrating Peptides; D009593:Nitroimidazoles; D010455:Peptides
cell-penetrating peptides; drug delivery; positron emission tomography (PET); proteolytic stability; tumor hypoxia; tumor theranostics