Most of current anticancer drugs have been developed in the past a half century and some of the combination therapies have proved to be active against some type of human malignancies, causing even cure cases. However, the efficacies are limited against solid cancers. Therefore, there are necessities to develop more effective and less toxic treatment regimens, finding more clinically useful drugs. In such circumstances, DDS studies have shown the significant values for finding more useful drugs. Recently many new type of drugs against molecular targets relating to cell-growth, apoptosis, metastases etc. have been studied. The author believes that these drugs against molecular targets also belongs to the category of new DDS studies. In the coming 21 st century, new active drugs may appear from DDS studies.

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The present status of the drug delivery system in the treatment of cancer was reviewed. Chemoembolization using mitomycin C entrapped in microcapsules of ethylcellulose for renal cell carcinoma and hepatocellular carcinoma were presented. Also, SMANCS dissolved in oily contrast medium Lipiodol for the treatment of hepatocellular carcinoma and chemoembolization using DSM(Degradable Starch Microsphere) were introduced. As an example of DDS for the slow release of drugs, the process of the development of copoly(DL-lactic/glycolic acid) microsphere leuprin was introduced. It is believed that immunotargeting therapy using antibody as a carrier of drug, biodegradable carriers, liposome technology and micromagnetite will be developd rapidly in 21^st century. The Japan Society of Drug Delivery System will make a great contribution to the development of new DDS in the future.

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Drug delivery system (DDS), currently employed for cancer gene therapy was reviewed. There have been at least four systems hitherto developed to deliver the anticancer genes to tumor. They include 1) modified liposome system such as cationic liposorne, HVJ-liposme, transferrin conjugated liposome etc. 2) naked plasmid DNA conjugated with ligand or antibody which are known to interact with receptor or antigen on tumor cells. 3) viral vectors such as retroviral vector, adenoviral vector, lenti viral vector, adenoassociated viral vector etc. 4) replication competent oncolytic viruses such as E 1 B attenuated adenovirus or genetically modified herpes simplex virus. Although most of these delivery systems are found to be applicable for local administration of transgene, little success has been reported as to specific targeting to tumor by systemic administration. Therefore efforts are now focusing on the development of devise to target tumor in vivo.

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Site-specific control of drug delivery to the tumor has been grately expected to achieve successful cancer chemotherapy by using carrier systems targeted to the tumor by controlling their in vivo physical and/or chemical interactions. For anticancer targeting systems, several types of drug carriers have been investigated. However, non-selective scavenging by the reticuloendothelial system is a serious problem even when carriers are monoclonal antibodies. Recently, the anticancer targeting systems are approched with the overall perspective of in vivo interactions of the targeted carrier with biocomponents including proteins, cells and organs as well as the binding affinities of the targeted carrier with cancer cells. The authors, herein, classify and explain the today's carrier systems for cancer chemotherapy into three categories : 1) Active targeting utilizing specific molecular recognition of antibodys or receptors, 2) Passive targeting achieved by controlling biodistribution of the carriers by regulating their pyhsical properties such as a size, hydrophilicity, charge, etc., and 3) Drug modulation using intelligent materials controlling drug biodistribution and/or drug bioactivity in response to external, physical stimuli such as temperature, light, magnetism, etc.. These systems are further developed by a conjunction of the systems resulting in amplification of the targeting efficacy. In order to achieve clinical application of these targeted carrier systems, interdisciplinary research of pharmaceutics, engineering and medicine must be required. Advanced science has been developing for design of the novel drug targeting system. In the future, progressive improvement of this area is expected to achieve effective cancer chemotherapy.

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Since the 1970's, a wide variety of cancer immunotherapies have been attempted, but to date none have been established as a general cancer therapy. We present here in data clearly indicating that Drug Delivery System (DDS) plays an important role in the establishment of cancer immunotherapy. Tumor necrosis factor-α (TNF-α)has been shown to exhibit striking cytotoxicity against various tumor cells in vitro, and has attracted attention as a potential anti-cancer drug. However, TNF-α is rapidly eliminated from blood circulation, and thus a very high dose is required to obtain a significant clinical anti-tumor effect. Systemic administration of TNF-α frequently induces toxic side-effects. Thus, cancer immunotherapy involving the use of TNF-α has been limited to local intra-tumoral administration. We previously reported that chemical modification of TNF-α with polyethylene glycol (PEG) prolonged its plasma half-life, and increased its and-tumor activity in the Meth-A marine model, Furthermore, we also synthesized TNF-α conjugated with divinely ether and maleic anhydride (DIVEMA), which is a biological response modifier that shows anti-tumor activity against various tumors. DIVEMA-TNF-α demonstrated a dramatic anti-tumor effect that was approximately 100 times greater than native TNF-α and was capable of inducing complete regression in all five mice bearing Meth-A solid tumors without causing any apparent side effects. In recent years, cancer vaccines have received a great deal of attention among various cancer immunotherapies. The major focus in cancer vaccine development has been on the generation of antigen specific cytotoxic T lymphocyte (CTL) responses. CTL recognizes antigens derived from endogenously expressed proteins present on the cell surface in the form of major histocompatibility complex(MHC)class I molecules. Moreover, the delivery of antigens to the class I pathway has been a matter of great importance to the development of cancer vaccines. Generation of CTL via immunization with exogenous proteins is often ineffective due to the fact that these Antigens typically enter the MHC class II pathway. We previously reported that fusogenic liposomes(FLs), prepared by simple fusion of liposomes with Sendai virus particle, fused with cell membranes and delivered their contents directly and efficiently into the cytoplasm both in vivo and in vitro. We show here that FLs as antigen carriers directly deliver into the class I pathway and effectively induce tumor-antigen specific CTL and anti-tumor effects.

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