Schmitt-Sody Marcus, Strieth Sebastian, Krasnici Senat, Sauer Birgitta, Schulze Brita, Teifel Michael, Michaelis Uwe, Naujoks Kurt, Dellian Marc
Institute for Surgical Research, Department of Otorhinolaryngology, Klinikum Grosshadern, University of Munich, 81377 Munich, Germany.
Clin Cancer Res. 2003 Jun;9(6):2335-41.
Cationic liposomes have been shown to selectively target tumor endothelial cells. Therefore, the encapsulation of antineoplastic drugs into cationic liposomes is a promising tool to improve selective drug delivery by targeting tumor vasculature. It was the aim of our study to evaluate tumor selectivity and antitumoral efficacy of paclitaxel encapsulated in cationic liposomes in comparison with the free drug paclitaxel (Taxol(R)) in vivo.
Experiments evaluating tumor selectivity were carried out in male Syrian golden hamsters bearing the amelanotic hamster melanoma A-Mel-3 in dorsal skinfold preparations. Growth of tumor cells was observed after s.c. inoculation (day 0). On days 5, 7, 9, 12, 14, and 16, animals were treated by continuous i.v. infusion over 90 min with 5% glucose, Taxol(R), unloaded cationic liposomes, or paclitaxel encapsulated into cationic liposomes (LipoPac), respectively (lipid dose, 150 mg/kg body weight; paclitaxel dose, 5 mg/kg body weight). Tumor volumes and presence of regional lymph node metastases were quantified.
Vascular targeting of rhodamine-labeled cationic liposomes was maintained after encapsulation of paclitaxel as revealed by in vivo fluorescence microscopy (ratio of dye concentration, tumor:normal tissue = 3:1). The s.c. tumor growth revealed a remarkable retardation of tumor growth after treatment with LipoPac (1.7 +/- 0.3 cm(3)). In contrast, control tumors showed exponential tumor growth [tumor volume at the end of the observation period (mean +/- SE): 5% glucose, 17.7 +/- 1.9 cm(3); unloaded cationic liposomes, 10.0 +/- 1.6 cm(3); Taxol(R), 10.7 +/- 1.7 cm(3)]. In addition, the appearance of regional lymph node metastases was significantly delayed by treatment with paclitaxel encapsulated into cationic liposomes in comparison with all other groups.
The data suggest that cationic liposomes are a powerful tool for selective and efficient drug delivery to tumor microvessels. This may serve as proof of the concept of neovascular tumor targeting therapy by cationic liposomes.
阳离子脂质体已被证明可选择性地靶向肿瘤内皮细胞。因此，将抗肿瘤药物包裹于阳离子脂质体中是一种通过靶向肿瘤血管来改善选择性药物递送的有前景的工具。我们研究的目的是在体内比较包裹于阳离子脂质体中的紫杉醇与游离紫杉醇（泰素）的肿瘤选择性和抗肿瘤疗效。
在雄性叙利亚金黄地鼠背部皮褶制备物中接种无黑色素的地鼠黑色素瘤A-Mel-3，进行评估肿瘤选择性的实验。皮下接种（第0天）后观察肿瘤细胞的生长情况。在第5、7、9、12、14和16天，动物分别通过静脉持续输注90分钟，给予5%葡萄糖、泰素、未载药的阳离子脂质体或包裹于阳离子脂质体中的紫杉醇（脂质体紫杉醇）（脂质剂量，150mg/kg体重；紫杉醇剂量，5mg/kg体重）。对肿瘤体积和区域淋巴结转移情况进行定量分析。
体内荧光显微镜检查显示，包裹紫杉醇后，罗丹明标记的阳离子脂质体对血管的靶向性得以维持（染料浓度比，肿瘤：正常组织 = 3:1）。皮下肿瘤生长情况显示，脂质体紫杉醇治疗后肿瘤生长明显迟缓（1.7±0.3cm³）。相比之下，对照肿瘤呈指数生长[观察期末肿瘤体积（平均值±标准误）：5%葡萄糖组，17.7±1.9cm³；未载药的阳离子脂质体组，10.0±1.6cm³；泰素组，10.7±1.7cm³]。此外，与所有其他组相比，包裹于阳离子脂质体中的紫杉醇治疗显著延迟了区域淋巴结转移的出现。
数据表明阳离子脂质体是一种向肿瘤微血管进行选择性和高效药物递送的有力工具。这可作为阳离子脂质体进行新生血管肿瘤靶向治疗概念的证据。
