Eichhorn M E, Luedemann S, Strieth S, Papyan A, Ruhstorfer H, Haas H, Michaelis U, Sauer B, Teifel M, Enders G, Brix G, Jauch K-W, Bruns C J, Dellian M
Department of Surgery and Institute for Surgical Research, Klinikum Grosshadern, University of Munich, Munich, Germany.
Cancer Biol Ther. 2007 Jun;6(6):920-9. doi: 10.4161/cbt.6.6.4207. Epub 2007 Mar 26.
Neo-vascular targeting by cationic colloidal carriers enables to realize an innovative approach for tumor therapy. EndoTag-2 is a novel vascular targeting agent, comprising the mammalian topoisomerase I inhibitor camptothecin in its carboxylate form complexed to cationic lipid (cationic lipid complexed camptothecin). Here we studied tumor vascular targeting properties, antitumoral effects and mode of action of EndoTag-2. Tumor vascular targeting properties of fluorescently labelled EndoTag-2 were investigated by in vivo microscopy using A-MEL-3 tumors grown in the dorsal skinfold chamber preparation and by fluorescence histology of s.c. LLC-1 carcinomas. Therapeutic effects have been investigated in the s.c. LLC-1 carcinoma model and the L3.6pl human pancreatic cancer model implanted orthotopically in athymic nude mice. Antivascular effects have been studied by histological investigation of tumor microvessel density and non invasive investigation of tumor blood flow by dynamic contrast enhanced MRI imaging (DCE-MRI). EndoTag-2 selectively targeted tumor microvessels as confirmed by quantitative fluorescence microscopy. Compared to controls EndoTag-2 revealed remarkable antitumoral efficiency in s.c. LLC-1 carcinomas implanted in C57/Bl6 mice. Growth and metastasis of orthotopic L3.6pl human pancreatic tumors was significantly inhibited by EndoTag-2 treatment. Quantitative analysis of tumor microvessel density revealed significant reduction of microvessel density in lewis lung carcinomas up to 50%. DCE-MRI confirmed significant reduction of intratumoral vascular volume as well as tumor perfusion upon EndoTag-2 treatment. In conclusion this study shows that cationic lipid complexed camptothecin (EndoTag-2) is a markedly active antitumor agent based on an innovative vascular targeting approach.
阳离子胶体载体的新血管靶向作用能够实现一种创新的肿瘤治疗方法。EndoTag-2是一种新型血管靶向剂，由羧酸盐形式的哺乳动物拓扑异构酶I抑制剂喜树碱与阳离子脂质复合而成（阳离子脂质复合喜树碱）。在此，我们研究了EndoTag-2的肿瘤血管靶向特性、抗肿瘤作用及作用方式。通过体内显微镜检查，利用在背部皮褶腔制备中生长的A-MEL-3肿瘤以及通过皮下LLC-1癌的荧光组织学，研究了荧光标记的EndoTag-2的肿瘤血管靶向特性。在皮下LLC-1癌模型以及原位植入无胸腺裸鼠体内的L3.6pl人胰腺癌模型中研究了治疗效果。通过肿瘤微血管密度的组织学研究以及动态对比增强磁共振成像（DCE-MRI）对肿瘤血流的无创研究，对血管生成抑制作用进行了研究。定量荧光显微镜检查证实，EndoTag-2可选择性地靶向肿瘤微血管。与对照组相比，EndoTag-2在植入C57/Bl6小鼠体内的皮下LLC-1癌中显示出显著的抗肿瘤效率。EndoTag-2治疗可显著抑制原位L3.6pl人胰腺肿瘤的生长和转移。肿瘤微血管密度的定量分析显示，Lewis肺癌中的微血管密度显著降低了50%。DCE-MRI证实，EndoTag-2治疗后肿瘤内血管体积以及肿瘤灌注显著减少。总之，本研究表明，阳离子脂质复合喜树碱（EndoTag-2）是一种基于创新血管靶向方法的具有显著活性的抗肿瘤药物。
