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      Use of Cyclic Backbone NGR-Based SPECT to Increase Efficacy of Postmyocardial Infarction Angiogenesis Imaging

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          Abstract

          As CD13 is selectively expressed in angiogenesis, it can serve as a target for molecular imaging tracers to noninvasively visualize angiogenic processes in vivo. The CD13-targeting moiety NGR was synthesized and cyclized by native chemical ligation (NCL) instead of disulfide bridging, leading to a cyclic peptide backbone: cyclo(Cys-Asn-Gly-Arg-Gly) (coNGR). Beside this new monomeric coNGR, a tetrameric NGR peptide co(NGR) 4 was designed and synthesized. After radiolabeling, their in vitro and in vivo characteristics were determined. Both coNGR-based imaging agents displayed considerably higher standardized uptake values (SUVs) at infarcted areas compared to the previously reported disulfide-cyclized cNGR imaging agent. Uptake patterns of 111In-coNGR and 111In-co(NGR) 4 coincided with CD13 immunohistochemistry on excised hearts. Blood stability tests indicated better stability for both novel imaging agents after 50 min blood incubation compared to the disulfide-cyclized cNGR imaging agent. In mice, both coNGR peptides cleared rapidly from the blood mainly via the kidneys. In addition, co(NGR) 4 showed a significantly higher specific uptake in infarcted myocardium compared to coNGR and thus is a promising sensitive imaging agent for detection of angiogenesis in infarcted myocardium.

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          Most cited references21

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          Angiogenesis in life, disease and medicine.

          The growth of blood vessels (a process known as angiogenesis) is essential for organ growth and repair. An imbalance in this process contributes to numerous malignant, inflammatory, ischaemic, infectious and immune disorders. Recently, the first anti-angiogenic agents have been approved for the treatment of cancer and blindness. Angiogenesis research will probably change the face of medicine in the next decades, with more than 500 million people worldwide predicted to benefit from pro- or anti-angiogenesis treatments.
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            Protein synthesis by native chemical ligation: expanded scope by using straightforward methodology.

            The total chemical synthesis of proteins has great potential for increasing our understanding of the molecular basis of protein function. The introduction of native chemical ligation techniques to join unprotected peptides next to a cysteine residue has greatly facilitated the synthesis of proteins of moderate size. Here, we describe a straightforward methodology that has enabled us to rapidly analyze the compatibility of the native chemical ligation strategy for X-Cys ligation sites, where X is any of the 20 naturally occurring amino acids. The simplified methodology avoids the necessity of specific amino acid thioester linkers or alkylation of C-terminal thioacid peptides. Experiments using matrix-assisted laser-desorption ionization MS analysis of combinatorial ligations of LYRAX-C-terminal thioester peptides to the peptide CRANK show that all 20 amino acids are suitable for ligation, with Val, Ile, and Pro representing less favorable choices because of slow ligation rates. To illustrate the method's utility, two 124-aa proteins were manually synthesized by using a three-step, four-piece ligation to yield a fully active human secretory phospholipase A(2) and a catalytically inactive analog. The combination of flexibility in design with general access because of simplified methodology broadens the applicability and versatility of chemical protein synthesis.
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              Angiogenesis: where do we stand now?

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                Author and article information

                Contributors
                Journal
                Contrast Media Mol Imaging
                Contrast Media Mol Imaging
                CMMI
                Contrast Media & Molecular Imaging
                Hindawi
                1555-4309
                1555-4317
                2017
                24 October 2017
                : 2017
                : 8638549
                Affiliations
                1Department of Radiology and Nuclear Medicine, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center (MUMC+), Maastricht, Netherlands
                2Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center (MUMC+), Maastricht, Netherlands
                3Department of Nuclear Medicine, University Hospital, RWTH University, Aachen, Germany
                4Department of Physiology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center (MUMC+), Maastricht, Netherlands
                Author notes

                Academic Editor: Barbara Palumbo

                Author information
                http://orcid.org/0000-0002-8176-1084
                http://orcid.org/0000-0003-4586-3646
                Article
                10.1155/2017/8638549
                5674494
                8a37c8f3-d50d-4a60-b5c0-b7be550cf76d
                Copyright © 2017 Geert Hendrikx et al.

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 29 May 2017
                : 9 September 2017
                : 19 September 2017
                Funding
                Funded by: CTMM
                Funded by: Weijerhorst Foundation
                Funded by: Nederlandse Organisatie voor Wetenschappelijk Onderzoek
                Categories
                Research Article

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