The significance of drug delivery systems of anticancer drug in surgical clinics is discussed. And drug delivery systems is divided into four categories ; DDS using unique rout and new device, DDS using modified anticancer drug formula, DDS utilizing specific circumstances of tumor tissue and DDS of gene therapy. DDS of anticancer drug practically applied for clinical use is introduced. And the future trend of DDS in cancer drug therapy will be disucussed.

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We have developed fusogenic liposomes with virus envelope proteins on the surface. These liposomes can introduce their contents (DNA, RNA, and protein) into cell cytoplasm directly by membrane fusion in vitro and in vivo. The liposomes can fuse with cell membrane as efficient as virus particles and can maintain their activity indefinitely in liquid nitrogen. Investigation of new system for future gene therapy is now under way based on these fusogenic liposomes.

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Reticuloendothelial system (RES)-avoiding liposomes having long circulating character have been expected for a useful drug carrier especially for a carrier of anticancer agents, since they tend to accumulate passively in tumor tissues. Liposomes modified with a uronic acid derivative, palmityl-glucuronide (PGlcUA), were developed previously for this purpose, PGlcUA-liposomes composed of dipalmitoylphosphatidylcholine, cholesterol, and PGlcUA remaining in the plasma for longer period of time than control liposomes containing dipalmitoytphosphatidylglycerol (DPPG) instead of PGLcUA. when these liposomes were administered intravenously into normal mice. Thus, the therapeutic efficacy of adriamycin encapsulated in PG1cUA-liposomes was examined using Meth A sarcoma-baring mice. Liposomal formulation, especially formulation of RES-avoiding liposomes, was efficient for reducing tumor growth and prolonging survival time. Therefore, PGlcUA-liposomes might be appropriate for practical usage as durg carriers of anticancer agents.

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Long-circulating, thrmosensitive liposomes (TSL, 200 nm in mean diameter) were prepared from GM1/DPPC/DSPC or PEG-PE/DPPC/DSPC. Doxorubicin (DXR) was encapsulated into GM1-TSL with >98% or PEG-TSL with >90% in trapping efficiency by pH gradient method, respectively. DXR was released from both type of TSL in a temperature-dependent manner in vitro. Inclusion of 6 mol% of GM1 or 3 mol% of PEG-PE endowed TSL with prolonged circulation ability resulting in increased blood levels of liposomes and decreased RES uptake after injection to mice. Concomitantly, high DXR levels in blood were maintained for long time. The combination of DXR-long-circulating TSL and the local hyperthermia have been tested for their utility as a temperature sensitive release for DXR in colon 26 tumor-bearing mice. Accumulation of DXR into tumor tissue by local hyperthermia after injection of DXR-long-circulating TSL was significantly higher than that of DXR-bare TSL or free DXR, and resulted in effective tumor growth retardation and increased survival time. These results indicate that long circulating ability is effective for thermosensitive liposomal drug delivery in combination with hyperthermia. This system is expected to be very useful for antitumor therapy.

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Several parameters have been established as important for the efficient delivery of liposomes-associated molecules. A non-exhaustive list includes parameters, such as size of liposomes, lipid composition, nature of the encapsulated molecule, the nature of the target molecule and the cell type expressing it. Of these, we studied size of liposomes and target molecules on human T lymphocytes. Liposomes, composed of dipalmitoylphosphatidylcholin, cholesterol and the modified phosphatidylethanolamine used to couple Protein A, were used as a model system to demonstrate drug transfer into specific lymphoid cells. Protein A, which selectively recognizes mouse IgG2 antibodies, was coupled to liposomes to target them specifically to defined cells types coated with IgG2 antibody. Methotrexate(MTX)-containing liposomes of different sizes (0.05, 0.1, or 0.2 μm), targeted to the major histocompatibility complex(MHC)-encoded class I molecules, were evaluated by their efficiency. It was clearly demonstrated that large liposomes are internalized by human lymphoid cells less well than smaller liposomes. And we have examined two T lymphocyte cell surface molecules, CD4 and CD7, as targets for specific drug delivery of drugs from targeted liposomes. CD? was shown to he a good target for drug delivery. But CD4 targeted liposomes, in contrast, was ineffective.

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A new dosage formulation (PEP-CH) composed of activated carbon particles adsorbing peplomycin, was examined for its macroscopic and microscopic pathological effects of subcutaneous adminstration in mice. Both formulations of PEP-CH and peplomycin aqueous solution (PEP-SOL) decreased the organ weights and the relative organ weights (organ weight/body weight) of the kidney and the spleen. These two formulations caused histological damages of the renal tubules and atrophy in the spleen and the thymus. Macroscopic and microscopic examination found no pathological changes in the lung exept for the slight congestion. There were no differences between these two formulations in the autopsy findings.

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Flurbiprofen (FP)-amino acid (L-arginine (Arg), L-lysine (Lys) and L-phenylalanine (Phe))ethyl esters were synthesized and the release of FP enantiomers from these compounds in the presence of trypsin (Tp), α-chymotrypsiin (ChTp)and carboxypeptidase (CP) A, CPR and CPY were examined. The ester bonds of these compounds were hydrolyzed rapidly by Tp or ChTp, suggesting that they are good substrates for these enzymes. FP(R) was released by CPB and CPY faster than FP (S) from the FP-basic amino acids, while FP-Phe-OH was not hydrolyzed at all by CPA. These results indicate the stereoselective carboxypeptidase-mediated release of FP enantiomers from the FP-basic amino acids. FP(S)-Arg-OH was separated from FP(R)-Arg-OH by high-performance liquid chromatography, The FP(S) was released by CPB and CPY from FP(S)-Arg-OH. it is therefore thought that FP(S)-Arg-OEt is utilized as an active water-soluble prodrug for FP.

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A cojugate(Lys-UDCA)of ursodeoxycholic acid (UDCA) with L-lysine was newly synthesized, and basic studies on this compound were carried out. In the incubation experiments with plasma, homogenates of the liver and small intestine, various pancreatic enzymes and cholylglycine hydrolase (CGH), carboxypeptidase B and CGH deconjugated Lys-UDCA. In the experiment using rodent everted gut sac, Lys-UDCA was actively absorbed from the terminal ileum. Conjugated (tauro-or glyco-UDCA) and free UDCA as well as Lys-UDCA were recovered well in the bile after intravenous or intraileal administration of Lys-UDCA in biliary fistula rat. Lys-UDCA showed less hemolytic action compared to tauro-UDCA and free UDCA. These data suggest that Lys-UDCA is a good prodrug of UDCA for intravenous administration.

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