Paclitaxel encapsulated in cationic liposomes increases tumor microvessel leakiness and improves therapeutic efficacy in combination with Cisplatin.

Abstract

Paclitaxel encapsulated in cationic liposomes (EndoTAG-1) is a vascular targeting formulation for the treatment of solid tumors. It triggers intratumoral microthrombosis, causing significant inhibition of tumor perfusion and tumor growth associated with endothelial cell apoptosis. Here, we quantified the effects of repeated EndoTAG-1 therapy on tumor microvascular leakiness with respect to leukocyte-endothelial cell interactions, the targeting property of cationic liposomes, and the therapeutic combination with conventional cisplatin chemotherapy. Using dorsal skinfold chamber preparations in Syrian Golden hamsters, in vivo fluorescence microscopy experiments were done after repeated EndoTAG-1 treatment of A-Mel-3 tumors. Controls received glucose, paclitaxel alone, or cationic liposomes devoid of paclitaxel. Extravasation of rhodamine-labeled albumin was measured to calculate microvessel permeability, and intratumoral leukocyte-endothelial cell interactions were quantified. Subcutaneous tumor growth was evaluated after combination therapy followed by histologic analysis. Microvascular permeability was significantly increased only after treatment with EndoTAG-1, whereas intratumoral leukocyte-endothelial cell interactions were not affected by any treatment. In separate skinfold chamber experiments, fluorescently labeled cationic liposomes kept their targeting property for tumor endothelial cells after repeated EndoTAG-1 treatment and no signs of extravasation were observed. Subcutaneous A-Mel-3 tumor growth was significantly inhibited by the combination of cisplatin and EndoTAG-1. These data show that vascular targeting with EndoTAG-1 increases tumor microvessel leakiness probably due to vascular damage. This mechanism is not mediated by inflammatory leukocyte-endothelial cell interactions. Manipulating the blood-tumor barrier by repeated tumor microvessel targeting using EndoTAG-1 can effectively be combined with tumor cell-directed conventional cisplatin chemotherapy.