Neovascular targeting chemotherapy: encapsulation of paclitaxel in cationic liposomes impairs functional tumor microvasculature.
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.
Strieth
Sebastian
S
Institute for Surgical Research, Klinikum Grosshadern, University of Munich, Marchioninistrasse 15, 81377 Munich, Germany.
Eichhorn
Martin E
ME
Sauer
Birgitta
B
Schulze
Brita
B
Teifel
Michael
M
Michaelis
Uwe
U
Dellian
Marc
M
D000818:Animals; D006224:Cricetinae; D004337:Drug Carriers; D004912:Erythrocytes / Q000187:drug effects; D020287:In Situ Nick-End Labeling; D008081:Liposomes; D008297:Male; D008546:Melanoma, Experimental / Q000098:blood supply* / Q000188:drug therapy* / Q000473:pathology; D008647:Mesocricetus; D008833:Microcirculation / Q000187:drug effects; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D017239:Paclitaxel / Q000008:administration & dosage*; D012039:Regional Blood Flow / Q000187:drug effects
D004337:Drug Carriers; D008081:Liposomes; D017239:Paclitaxel