35 years of discussions with Prof. Maeda on the EPR effect and future directions.

In May 2021, 35 years after first announcing the enhanced permeability and retention (EPR) effect, Dr. Maeda passed away. As a theoretical pillar of high molecular weight drug delivery systems (DDS) with high biocompatibility, the EPR effect has been proven worldwide in experimental mouse models. However, in clinical solid tumors, awareness of the EPR effect is insufficient, and more importantly, DDS has not become the mainstream cancer treatment. Both Dr. Maeda and I were acutely aware of this, and for 35 years, we discussed what to do about it and strived to make up for the inadequacies of the EPR effect by employing different strategies. Dr. Maeda came up with ways to use tumor vascular permeability more effectively and to apply oxidative stress to tumor cells. I proposed cancer stromal targeting (CAST) therapy using the anti-insoluble fibrin antibody conjugated with an anticancer agent in order to overcome the insufficiency of the EPR effect in clinical solid cancers, which possess abundant stromal tissue. Clinical cancers are surrounded by an abundant stroma and survive even under hypoxia and malnutrition due to this stromal barrier. Cancer cells become resistant to any external attack, including with anticancer drugs and radiation. While it goes without saying that EPR effects are important in clinical solid cancer strategies, DDSs that offer both accumulation and even distribution in solid cancers are also required.