| Literature DB >> 23496322 |
Christian Schwöppe1, Caroline Zerbst, Max Fröhlich, Christoph Schliemann, Torsten Kessler, Ruediger Liersch, Laura Overkamp, Richard Holtmeier, Jörg Stypmann, Alena Dreiling, Simone König, Carsten Höltke, Martin Lücke, Carsten Müller-Tidow, Rolf M Mesters, Wolfgang E Berdel.
Abstract
tTF-NGR consists of the extracellular domain of tissue factor and the peptide GNGRAHA, a ligand of the surface protein aminopeptidase N and of integrin αvβ3. Both surface proteins are upregulated on endothelial cells of tumor vessels. tTF-NGR shows antitumor activity in xenografts and inhibition of tumor blood flow in cancer patients. We performed random TMS(PEG)12 PEGylation of tTF-NGR to improve the antitumor profile of the molecule. PEGylation resulted in an approximately 2-log step decreased procoagulatory activity of the molecule. Pharmacokinetic studies in mice showed a more than 1-log step higher mean area under the curve. Comparison of the LD10 values for both compounds and their lowest effective antitumor dose against human tumor xenografts showed an improved therapeutic range (active/toxic dose in mg/kg body weight) of 1/5 mg/kg for tTF-NGR and 3/>160 mg/kg for TMS(PEG)12 tTF-NGR. Results demonstrate that PEGylation can significantly improve the therapeutic range of tTF-NGR.Entities:
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Year: 2013 PMID： 23496322 DOI： 10.1021/jm301669z
Source DB: PubMed Journal: J Med Chem ISSN： 0022-2623 Impact factor: 7.446