Hiroshi Maeda
Posters-Accepted Abstracts: Chemotherapy
Cancer is the largest human burdens in health issue. However, its therapy has not really improved much even after emergence of molecular target-drugs, antibody-drugs, liposomal or polymeric micellar-drugs, etc. We proposed a new concept of cancer drugs 30 years ago using macromolecular drugs (nanomedicines). In this concept the tumor vasculature is the target, which depends on the uniquely different pathophysiology, contrary to normal, such as micro-architecture, excessive production of vascular mediators like bradykinin and NO, and impaired lymphatic clearance from tumor bed. This concept named enhanced permeability and retention (EPR) effect is the basis of tumor-selective drug delivery. This is observed for biocompatible macromolecular-drugs of >50 KDa. It covers, however, only the first step in tumor-delivery, yet it is most critical. Second step is access to tumor cells. The third step is tumor cell-uptake. In the second step, liberation of low-MW-drugs occurs from nanoparticle facilitating rapid diffusion to tumor cell-membrane. In the third step, one can utilize upregulated glucose-transporter for internalization. We developed recently polymer- (HPMA)-conjugated pirarubicin (THP) via hydrazon bond, which is more selectively cleaved in acidic tumor environment, and liberated the low MW drug which is rapidly taken up into tumor cells more than 30 x of doxorubicin. Using this conjugate our preliminary clinical results showed to be very promising. In drug-dose below toxic level, it exhibits remarkable therapeutic effect. In many solid tumors, blood vessels are frequently embolized and blood flow is hampered. To circumvent this and enhance the EPR effect, we found use of nitroglycerin and inhibitors of angiotensin converting enzyme is highly beneficial, that facilitate tumor drugdelivery 2-3 fold. The EPR effect is also observed in metastatic tumors and inflamed tissues. All in all there are more to come for nanomedicine in cancer therapy, and enhancement of EPR will be highly recommended for tumor delivery without involving serious adverse effects.
