Targeted Liposomal Paclitaxel Raises Tumor Vessel Leakiness

Abstract

Problem

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.

Methods

Using dorsal skinfold chamber preparations in Syrian Golden hamsters in vivo fluorescence microscopy experiments were performed after repeated EndoTAG-1 treatment of A-Mel-3 tumors. Controls received glucose, paclitaxel alone or cationic liposomes devoid of paclitaxel. Extravasation of rhodamine-labelled 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 histological analysis.

Results

Microvascular permeability was significantly increased only after treatment with EndoTAG-1, while 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.

Conclusion

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.

Significance

Antivascular therapy using liposomal paclitaxel (EndoTAG-1) is currently undergoing Phase II clinical studies in human cancer patients. Referring to the present experimental data showing increased permeability of intratumoral microvessels combination therapy with conventional therapy appears to be a very promising strategy.

Support

This study was supported by grants of Munich Biotech AG, Neuried, Germany and by grants of the Novartis Foundation for Therapeutic Research, Nürnberg, Germany.