Strieth Sebastian, Eichhorn Martin E, Sauer Birgitta, Schulze Brita, Teifel Michael, Michaelis Uwe, Dellian Marc
Institute for Surgical Research, Klinikum Grosshadern, University of Munich, Marchioninistrasse 15, 81377 Munich, Germany.
Int J Cancer. 2004 May 20;110(1):117-24. doi: 10.1002/ijc.20083.
Cationic liposomes have been shown to be internalized selectively by angiogenic tumor endothelial cells after intravenous injection. Therefore, encapsulation of cytotoxic substances in cationic liposomes is a new approach to target tumor vasculature. It was the aim of our study to quantify the effects of paclitaxel encapsulated in cationic liposomes (MBT-0206) on tumor microvasculature and growth in vivo. Experiments were performed in the dorsal skinfold chamber preparation of Syrian Golden hamsters bearing syngeneic A-Mel-3 melanomas. Tumors were treated with intravenous infusion of MBT-0206 (20 mM) resulting in an effective paclitaxel dose of 5 mg/kg body weight (b.w.). Control animals received conventional paclitaxel in Cremophor EL (Taxol(R); 5 mg/kg b.w.), unloaded cationic liposomes (20 mM) or the solvent 5% glucose, respectively. Using intravital microscopy, tumor growth and effects on intratumoral microvasculature were analyzed. Tumor growth was significantly retarded after treatment with MBT-0206 compared to the treatment with paclitaxel. Analysis of intratumoral microcirculation revealed a reduced functional vessel density in tumors after application of liposomal paclitaxel. At the end of the observation time, vessel diameters were significantly smaller in animals treated with paclitaxel encapsulated in cationic liposomes while red blood cell velocity was less affected. This resulted in a significantly reduced blood flow in vessel segments and a reduced microcirculatory perfusion index in these animals. Histochemical TUNEL stain was vessel-associated after treatment with liposomal paclitaxel in contrast to few apoptotic tumor cells in the control groups. Our data demonstrate that encapsulation of paclitaxel in cationic liposomes significantly increased the antitumoral efficacy of the drug. Remarkable microcirculatory changes indicate that encapsulation of paclitaxel in cationic liposomes resulted in a mechanistic switch from tumor cell toxicity to an antivascular therapy.
阳离子脂质体经静脉注射后已被证明可被血管生成性肿瘤内皮细胞选择性内化。因此，将细胞毒性物质包裹在阳离子脂质体中是一种靶向肿瘤血管系统的新方法。我们研究的目的是量化包裹在阳离子脂质体（MBT - 0206）中的紫杉醇对肿瘤微血管系统和体内生长的影响。实验在携带同基因A - Mel - 3黑色素瘤的叙利亚金仓鼠背部皮褶腔制备模型中进行。肿瘤通过静脉输注MBT - 0206（20 mM）进行治疗，有效紫杉醇剂量为5 mg/kg体重（b.w.）。对照动物分别接受溶于聚氧乙烯蓖麻油（Taxol®；5 mg/kg b.w.）的传统紫杉醇、未负载药物的阳离子脂质体（20 mM）或溶剂5%葡萄糖。使用活体显微镜，分析肿瘤生长以及对肿瘤内微血管系统的影响。与紫杉醇治疗相比，MBT - 0206治疗后肿瘤生长显著减缓。肿瘤内微循环分析显示，应用脂质体紫杉醇后肿瘤内功能性血管密度降低。在观察期结束时，用阳离子脂质体包裹紫杉醇治疗的动物血管直径明显较小，而红细胞速度受影响较小。这导致这些动物血管段的血流显著减少，微循环灌注指数降低。与对照组中很少有凋亡肿瘤细胞相比，脂质体紫杉醇治疗后组织化学TUNEL染色与血管相关。我们的数据表明，将紫杉醇包裹在阳离子脂质体中显著提高了该药物的抗肿瘤疗效。显著的微循环变化表明，将紫杉醇包裹在阳离子脂质体中导致了从肿瘤细胞毒性到抗血管治疗的机制转变。
