Department of Medicine A, Hematology, Oncology and Pneumology, University of Muenster , Albert-Schweitzer-Campus 1, D-48129 Muenster, Germany.
J Med Chem. 2013 Mar 28;56(6):2337-47. doi: 10.1021/jm301669z. Epub 2013 Mar 15.
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.
tTF-NGR 由组织因子的细胞外结构域和肽 GNGRAHA 组成，GNGRAHA 是表面蛋白氨肽酶 N 和整合素 αvβ3 的配体。这两种表面蛋白在肿瘤血管的内皮细胞中均上调。tTF-NGR 在异种移植中具有抗肿瘤活性，并能抑制癌症患者的肿瘤血流。我们对 tTF-NGR 进行了随机 TMS(PEG)12 PEG 化，以改善该分子的抗肿瘤特性。PEG 化导致该分子的促凝活性降低约 2 个对数级。在小鼠中的药代动力学研究表明，平均曲线下面积（AUC）提高了 1 个以上对数级。比较两种化合物的 LD10 值及其对人肿瘤异种移植物的最低有效抗肿瘤剂量表明，tTF-NGR 的治疗范围（以 mg/kg 体重计的活性/毒性剂量）改善为 1/5mg/kg，而 TMS(PEG)12 tTF-NGR 的治疗范围为 3/>160mg/kg。结果表明，PEG 化可以显著改善 tTF-NGR 的治疗范围。
