Enhanced vascular permeability of tumor and angiogenesis both sustain tumor growth mediated by many vascular mediators and high vascular density. Impaired reticuloendothelial/lymphatic clearance of macromolecules from the tumor, or lack of such clearance, is another unique characteristic of tumor tissue (Fig. 9). The enhanced permeability and retention (EPR) effect is the basis for the selective targeting of macromolecular drugs to tumor, and the EPR concept is now utilized for selective delivery of macromolecular anticancer agents, which is not possible for low-molecular-weight drugs because of rapid washout by capillary blood flow. This EPR concept has been validated in clinical settings with hepatoma and other solid tumors (7, 12, 49-52, 54, 56). More recently, HPMA-copolymer conjugated PK-1 has also demonstrated this effect (12, 34, 57). More efficient drug delivery to tumor, especially of macromolecular drugs, may be possible by enhancing the EPR effect with the use of various vascular permeability mediators or potentiators. Suppression of the EPR effect by the use of appropriate inhibitors or antidotes, such as the bradykinin antagonist HOE 140 and protease inhibitors or NOS inhibitors, may also be possible. Thus, one may be able to suppress or retard tumor growth and tumor metastasis. Also, by suppressing vascular permeability with antidotes such as the bradykinin antagonist HOE 140, pleural fluid in lung cancer and ascitic fluid in abdominal carcinomatosis may be controlled and the clinical course of cancer patients may be improved. Arterial infusion of Lipiodol will be by far the best targeting method, in that a tumor/blood ratio of >2000 can be achieved, which is considerably better than that obtained with monoclonal antibody (which is actually not much better than that seen with intravenously injected polymeric drugs in general). In summary, tumor vasculature can be an excellent target for delivery of macromolecular anticancer drugs, the most beneficial class of drugs in view of tumor-selective targeting based on the EPR effect in solid tumor (7, 8, 12, 36, 49-53, 55-58).
