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Experimental Therapeutics, Preclinical Pharmacology |
Institute for Surgical Research, Department of Otorhinolaryngology, Klinikum Großhadern, University of Munich, 81377 Munich, Germany [M. S-S., S. S., S. K., M. D.], and Munich Biotech AG, 82061 Neuried, Germany [B. Sa., B. Sc., M. T., U. M., K. N.]
Purpose: 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®) in vivo.
Experimental Design: 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®, 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.
Results: 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 cm3). 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 cm3; unloaded cationic liposomes, 10.0 ± 1.6 cm3; Taxol®, 10.7 ± 1.7 cm3]. 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.
Conclusions: 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.
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