Zinostatin Stimalamer

Hepatic diseases are turning into one of the few diseases that cannot be effectively cured due to some reasons although various receptors existed in the liver. Currently, several passive targeting delivery systems have been used in the drug/gene delivery for the treatment of hepatic diseases. For example, Zinostatin stimalamer (trade name of Smancs(®)), a drug-polymer conjugate, was launched in Japan in 1994, which treats hepatocellular carcinoma. More improtantly, different measures would be taken in accord to the specified cell that was lesioned or dysfunctioned via interaction between homing ligands and target receptors so as to improve accumulation of drugs in the target cell and to reduce nonspecific toxicity towards other cells or organs. Therefore, it is urgent to design novel delivery systems that physically or chemically grafted homing devices in order to improve the targeting properties of drugs in specific cell sites. From that perspective, the present article highlights recent development of active hepatic targeting drug/gene delivery systems for the treatment of hepatic diseases that were mediated by some kinds of receptors including asialoglycoprotein receptors (ASGP-R), glycyrrhetinic acid receptor (GA-R), glycyrrhizin receptor (GL-R), hyaluronan receptor (HA-R) and so on.

In this review, I have discussed various issues of the cancer drug targeting primarily related to the EPR (enhanced permeability and retention) effect, which utilized nanomedicine or macromolecular drugs. The content goes back to the development of the first polymer-protein conjugate anticancer agent SMANCS and development of the arterial infusion in Lipiodol formulation into the tumor feeding artery (hepatic artery for hepatoma). The brief account on the EPR effect and its definition, factors involved, heterogeneity, and various methods of augmentation of the EPR effect, which showed remarkably improved clinical outcomes are also discussed. Various obstacles involved in drug developments and commercialization are also discussed through my personal experience and recollections.