Figure 1.

(A) A diagram of normal and tumor tissue, demonstrating the presence of a lymphatic duct in normal tissue (upper) but the absence of any lymphatic duct in tumor tissue (lower). Small molecules easily leak from normal vessels in the body, which gives small molecules a short plasma half life. On the other hand, macromolecules have a long plasma half life because they are too large to pass through the normal vessel walls, unless they are trapped by the reticuloendothelial system in various organs. In the solid tumor tissues shown in the lower panel, it was found that solid tumors generally possess several pathophysiological characteristics: hypervasculature, secretion of vascular permeability factors stimulating extravasation of macromolecules within the cancer, and absence of effective lymphatic drainage from tumors that impedes the efficient clearance of macromolecules accumulated in solid tumor tissues. These characteristics of solid tumors are the basis of the enhanced permeability and retention (EPR) effect. Summarizing these findings, conventional low‐molecular‐weight anticancer agents disappear before reaching the tumor tissues and exerting their cell‐killing effect. On the other hand, macromolecules and nanoparticles including micelle carriers should have time to reach the tumor, extravasate from the tumor capillaries, and stay for a long time in the tumor tissue, by means of the EPR effect. (B) Example of the EPR effect. This in vivo imaging demonstrates that both control whole immunoglobulin G (IgG) and the specific whole monoclonal antibody (mAb) accumulated selectively in the tumor tissue on day 1 after invravenous injection. On day 7, a greater degree of retention of the specific whole mAb as compared to the control IgG was noted. On the other hand, the F(ab) region of the specific mAb with a molecular weight of 45 000 accumulated in the tumor to the same extent as the control whole IgG. Interestingly, fluorescence of the F(ab) could also be detected in both the kidneys, which implied that the antigen binding fragment F(ab) could easily pass through the kidney glomerulus. This accumulation of the control IgG in the tumor represents the EPR effect. The findings suggest that not only the specific affinity of the mAb, but also the size of the molecules and the stability of the molecules in blood are important for tumor‐selective targeting.