Effekt von Paclitaxel verpackt in kationische Liposomen auf Wachstum und Metastasierung solider Tumoren in vivo

Abstract

Introduction: Cationic liposomes have been shown to accumulate preferentially at sites of angiogenesis [1]. This property potentially enables improved drug delivery to tumor vasculature and tumor cells. The aim of our study was to evaluate the antitumoral efficacy of paclitaxel encapsulated in cationic liposomes in comparison to paclitaxel dissolved in alcoholic cremophor EL (Taxol) in vivo. Methods: Experiments were carried out in male Syrian golden hamsters (40 – 50 g body weight) bearing the s.c. inoculated amelanotic hamster melanoma A-Mel-3. On day 5 after inoculation, when tumors had reached a volume of approximately 120 mm³ , animals were randomized into four groups (n = 6). Animals in a control group were treated with vehicle (5% glucose). A second group received cationic liposomes (5 ml/kg body weight, 50 mM, ∅ 200 nm) without paclitaxel. The animals in groups 3 and 4 were treated with paclitaxel dissolved in cremophor EL or encapsulated in cationic liposomes, respectively, starting at day 5 after tumor inoculation until day 15 (5 mg paclitaxel/kg body weight by i.v. injection). Tumor volumes, animal weight and presence of axillar and inguinal lymph node metastases were quantified in 2-day intervals, beginning at day 5 after tumor inoculation. Results: In comparison to control tumors showing exponential growth, a significant reduction of tumor volume was observed in the hamsters treated with paclitaxel dissolved in cremophor EL or cationic liposomes alone (p < 0.05). However, application of cationic liposome encapsulated paclitaxel resulted in a significant further reduction of tumor growth. Tumor volumes at day 23 after inoculation: 17.7 cm³ ± 1.9 cm³ (glucose 5%); 10.0 cm³ ± 1.6 cm³ (cationic liposomes); 10.7 cm³ ± 1.7 cm³ (paclitaxel dissolved in cremophor EL); 1.7 cm³ ± 0.3cm³ (cationic liposome encapsulated paclitaxel); (MW ± SEM). In addition, the development of metastases was markedly delayed (p < 0.05) upon treatment with paclitaxel encapsulated in cationic liposomes as compared to all other groups. Conclusion Encapsulation of paclitaxel into cationic liposomes resulted in enhanced retardation of tumor growth and metastases in vivo. Our data suggest that encapsulation of antitumoral substances into cationic liposomes may allow their therapeutic efficacy to be improved, possibly by a direct antiangiogenic effect on tumor endothelium.