Universität zu Köln

Bergmann, Ralf, Splith, Katrin, Pietzsch, Jens ORCID: 0000-0002-1610-1493, Bachmann, Michael ORCID: 0000-0002-8029-5755 and Neundorf, Ines ORCID: 0000-0001-6450-3991 (2017). Biological characterization of novel nitroimidazole-peptide conjugates in vitro and in vivo. J. Pept. Sci., 23 (7-8). S. 597 - 610. HOBOKEN: WILEY. ISSN 1099-1387

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Abstract

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 with Cu-64(II) and Ga-68(III), 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 (c) 2017 European Peptide Society and John Wiley & Sons, Ltd.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Bergmann, Ralf UNSPECIFIED UNSPECIFIED UNSPECIFIED Splith, Katrin UNSPECIFIED UNSPECIFIED UNSPECIFIED Pietzsch, Jens UNSPECIFIED orcid.org/0000-0002-1610-1493 UNSPECIFIED Bachmann, Michael UNSPECIFIED orcid.org/0000-0002-8029-5755 UNSPECIFIED Neundorf, Ines UNSPECIFIED orcid.org/0000-0001-6450-3991 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-225625
DOI:	10.1002/psc.2995
Journal or Publication Title:	J. Pept. Sci.
Volume:	23
Number:	7-8
Page Range:	S. 597 - 610
Date:	2017
Publisher:	WILEY
Place of Publication:	HOBOKEN
ISSN:	1099-1387
Language:	English
Faculty:	Faculty of Mathematics and Natural Sciences
Divisions:	Faculty of Mathematics and Natural Sciences > Department of Chemistry > Institute of Biochemistry
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language CELL-PENETRATING PEPTIDES; LOCAL TUMOR-CONTROL; HYPOXIA; RADIOPHARMACEUTICALS; TISSUE; PET; CYTOTOXICITY; COMPLEXES; CU-64 Multiple languages Biochemistry & Molecular Biology; Chemistry, Analytical Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/22562