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Cationic lipid complexed paclitaxel (EndoTAG™-1) is a novel vascular targeting agent for the treatment of cancer. Here, the aim was to investigate intratumoral drug distribution after EndoTAG™-1 therapy and analyze the impact of EndoTAG™-1 scheduling on antitumoral efficacy. The therapeutic effect of EndoTAG™-1 in combination with conventional gemcitabine or cisplatin therapy was evaluated in L3.6pl orthotopic pancreatic cancer and a subcutaneous Lewis lung (LLC-1) carcinoma model. Oregon Green paclitaxel encapsulated in cationic liposomes in combination with intravital fluorescence microscopy clearly exhibited delivery of the drug by EndoTAG™-1 to the tumor endothelium, whereas Oregon Green paclitaxel dissolved in cremophor displayed an interstitial distribution pattern. The therapeutic efficacy of EndoTAG™-1 was critically dependent on the application schedule with best therapeutic results using a metronomic rather than a maximum tolerated dose application sequence. The combination of EndoTAG™-1 therapy and cytotoxic chemotherapy significantly enhanced antitumoral efficacy in both tumor models. Interestingly, only EndoTAG™-1 in combination with gemcitabine was able to inhibit the incidence of metastasis in pancreatic cancer. In conclusion, vascular targeting tumor therapy by EndoTAG™-1 combined with standard small molecular chemotherapy results in markedly enhanced antitumoral efficacy. Therefore, this combination represents a promising novel strategy for clinical cancer therapy.