Anticancer Therapy by Tumor Vessel Infarction with Polyethylene Glycol Conjugated Retargeted Tissue Factor

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• 作者：Christian Schw枚ppe ; Caroline Zerbst ; Max Fr枚hlich ; Christoph Schliemann ; Torsten Kessler ; Ruediger Liersch ; Laura Overkamp ; Richard Holtmeier ; J枚rg Stypmann ; Alena Dreiling ; Simone K枚nig ; Carsten H枚ltke ; Martin L眉cke ; Carsten M眉ller-Tidow ; Rolf M. Mesters ; Wolfgang E. Berdel
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：March 28, 2013
• 年：2013
• 卷：56
• 期：6
• 页码：2337-2347
• 全文大小：485K
• 年卷期：v.56,no.6(March 28, 2013)
• ISSN：1520-4804

文摘

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 伪_v尾₃. 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.