A trend in recent researches on a development of drug delivery system (DDS) was described. Some problems of existing DDS are discussed from pharmacetical point of view. Recent researches concerning development of intragastric buoyant preparations and magnetically conducted targeting are also pointed out.

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Two kinds of glucose-sensitive insulin-releasing systems were developed. The first system is based on changes in pH, induced by an enzyme, in response of glucose. The other is based on redox reaction, catalyzed by an enzyme, in response to glucose. 1) Glucose oxidase (GOD) is immobilized on a poly (acrylic acid)-grafted porous cellulose membrane, which is prepared as a pH-sensitive membrane. In the absence of glucose, the chains of poly (acrylic acid)-grafts are rod-like, lowering the porosity of the membrane and suppressing insulin permeation. On the other hand, in the presence of glucose, gluconic acid, produced by GOD, protonates the poly (acrylic acid), making the graft chains coil-like and the pores open to enhance insulin permeation. 2) Insulin is immobilized on a membrane through disulfide bond, NAD and FAD are also coimmobilized on the membrane. When glucose is added, glucose dehydrogenase catalyzes oxidation of the glucose. Electrons, which are produced during the reaction, are transported, and subsequently they reduce the disulfide bonds. Consequently the immobilized insulin is released.

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Anti-idiotypic monoclonal antibodies(MoAbs) were prepared against anti-CEA monoclonal anti-body 5B3 which reacted with the carbohydrate moiety on CEA. Anti-idiotypic MoAbs recognized the private idiotype on MoAb 5B3. Idiotype mapping of MoAb 5B3 showed that there might be at least three idiotopes on the combining site of it. Three different anti-idiotypic MoAbs could induce anti-anti-idiotypic antibodies specific to immunizing anti-idiotypic MoAb respectively. Two anti-anti-idiotypic antibodies out of three might have the same reactivity as that of MoAb 5B3 to CEA. The results suggest that an anti-idiotypic antibody bearing internal image of tumor associated antigen may induce the anti-anti-idiotypic antibodies specific to tumor associated antigen and it may be useful for cancer therapy.

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The disposition and tumor localization of model macromolecules with the same molecular weight but different electric charge were studied in sarcoma 180 bearing mice. Dextran (T-70) with molecular weight of 70, 000, cationic DEAE-dextran (T-70), anionic CM-dextran (T-70), bovine serum albumin(BSA), and cationized BSA (cBSA)were injected intravenously and their tissue distribution was determined by radioactivity counting. The cationic macromolecules were rapidly cleared from plasma and accumulated in the liver, and spleen or excreted into urine, while tumor levels remained low. On the contrary, anionic macromolecules were retained in the plasma for a long time and slowly accumulated to the tumor. The present study revealed that macromolecules having an anionic charge are advantageous for tumor targeting.

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We examined the effects of liposomal size, charge and cholesterol content on growth of NIH3T3 cells. Large doses of liposomes were found to inhibit the cell growth. Among the liposomes containing the charged compounds, stearylaminecontaining liposomes completely inhibited cell growth at 100 μM and were more potent in inhibition of cell growth than those with negative charged compounds. The cholesterol-rich and small unilamellar vesicles were more inhibitory for cell growth compared to the cholesterol-poor and multilamellar ones. The binding assay of liposomes with cells showed a good correlation with the degree of cell growth inhibition, These results indicate that the direct effect of liposomes should be considered for analysis of the effectiveness of the drug-containing liposomes.

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Liposomes can be designed to release entrapped drugs preferentially at their liquid-crystalline phase transition temperature (Tc). We have reported the enhanced antitumor effect of temperature-sensitive liposomes containing adriamycin (TS-Lip-ADM) made of DPPC (Tc=41°C) with local tumor hyperthermia (LTH). The selective delivery of ADM from TS-Lip-ADM to NUE human hepatoma cells inoculated in bilateral rear feet of nude mice and organ distribution were studied, compared with ADM alone (free ADM) and non-temperature-sensitive liposomes containing ADM (Lip-ADM). A right foot was heated at 42°C for 30 min after drug injection. The release rate of ADM from TS-Lip-ADM proved to be dependent on the change of temperature. The tumor uptake of ADM from TS-Lip-ADM with LTH was about three times as high as other heated groups, and six times as the unheated groups. Liposomal ADM accumulated in RES organs such as liver and spleen, and concentrations of free ADM in kidney, lung and heart were higher than liposomal ADM. Under anesthesia, ADM concentration of TS-Lip-ADM in serum was much higher than other groups, and decreased with LTH. In these three conditions liposomal ADM concentration was lower in heart, and higher in serum than free ADM. These results sugests that this thermochemotherapy will be useful for anti-cancer targeting therapy.

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We developed a new apparatus to inject anticancerous drug into the peritoneum by high pressure water jet. The principle of this method is that minute water particles containing high-dose anticancerous drugs developed by nozzle, which connected the water pump, are administered to the peritoneum. After the injection of Cisplatinum (CDDP) using this apparatus, pharmacokinectics of CDDP was studied. The platinum concentration of peritoneal tissue in treated rats was 5 to 35 times larger than that of control rats, received intraperitoneal injection of the same dose of CDDP. In addition, the free CDDP in peripheral blood could not be detected thoughout the experiment. Three cases of gastric cancer with peritoneal dissemination were treated by this method. Two of them disclosed the complete disappearance of ascites. These results indicate that this novel method is useful to treat the peritoneal dissemination of various carcinomas.

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New liquid crystal-immobilized membrane (LC-membrane) was prepared to develop the thermo-responsive drug delivery systems, This LC-membrane has high compatibility to a variety of drugs because of its electrical neutrality and the LC can sharply control the membrane permeation of drugs in response to temperature. The application of thermo-responsive LC-membrane to transdermal delivery of glyceryl trinitrate (GTN) and isosorbide dinitrate (ISDN) was studied to achieve the on-off switching release of the vasodilators which reguire “wash-out” from the body to avoid drug tolerance. The permeability of GTN and ISDN through LC-membrane increased above the gel-liquid crystal phase trandition temperature (Tc) of LC(38°C), The LC-membrane suppressed GTN and ISDN permeation through the excised abdominal skin of hairless rat at 32°C to about one-half of that at 38°C Similar tendency was found in the plasma level of GTN and ISDN in hairless rat. It was suggested from these results that the LC-membrane might enable Transdermal Therapeutic Systems to achieve the on-off switching release.

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We established the preparative method of suspension of cisplatin in Lipiodol (LPS) and challenged intra-hepatic artery injectional chemotherapy with LPS for the treatment of hepatocellular carcinoma. Thirty-one patients were classified into Stage I(1), II(10), III(11)and IV(9 cases), respectively, and LPS of 20-150 mg was administrated after injection of angiotensin II via hepatic artery. Then, PR in 14 cases (45%), MR in 13 cases (42%), and NC in 4 cases (13%) were obtained, α-fetoprotein levels in all 15 cases (AFP>400 ng/ml) decreased and the mean decreasing rate was 74.3%. The peaks of plasma platinum (Pt) concentrations determinated as non protein bound Pt were obtained in 5-20 minutes and 5-60 minutes as total Pt after the end of injection of LPS. Pt concentrations in the tumor tissues were 42.0 times higher in 4 operated cases and 7.1 times higher in 6 autopsy cases than those in non-tumor tissues. Marked decrease in tumor size as well as tumor markers revealed excellent effects of this therapy, and the results of measurement of Pt concentrations in plasma and in tumor tissue indicated that LPS had characteristically long and selective pooling in hepatocellular carcinoma.

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We have evaluated the antitumor effect of IL-2 mini-pellet on the therapy of murine Meth-A sarcoma. After the administration of IL-2 mini-pellet containing 1×10⁶u of IL-2, the serum IL-2 activity was detectable for 72 hours. The s. c. administration of IL-2 mini-pellet and the i. v. injection of LAK cells was effective in inhibiting the tumor growth and could also prolong the survivals. The lytic activites of splenocytes against YAC-1 cells and JTC-11 cells after the administration of IL-2 mini-pellet were augmented. In histological examination on day 7 after the administration of IL-2 mini-pellet, a lot of lymphocytes were invased into tumor tissues. These results suggest that IL-2 mini-pellet can be applied to the adoptive immunotherapy using LAK cells.

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Exogeneous cholic acid is known to be absorbed from the small intestine and then maintained within the enterohepatic circulation. A noble compound, CA 102(a conjugate of cholic acid which could be a carrier of anticancer agents with an alkylating agent, bis-(chloroethyl)glycine was synthesized. The antitumor activity of CA 102 was characterized in vitro and in vivo using intraportal, s. c. and i. p. implanted colon 26 and other experimental ascitic tumors including S 180, Ehrlich, P 388, M 5076. It was shown that CA 102 itself had alkylating and cytocidal activity by reaction with 4-(4-nitrobenzyl) pyridine and by growth inhibition of cultured L 1210 cells, respectively. Intraperitoneal administration of CA 102 showed strong antitumor activity in experimental ascitic tumors. And CA 102 had strong antitumor activity by p. o. administration in intraportal implanted colon 26 but had no activity in s. c. and i. p. implanted colon 26. Acute toxicity of CA 102 was examined in mice. The high value of LD₅₀ (more than 2, 000 mg/kg(p. o.))comparing with other antitumor drugs with direct alkylating and cytocidal activities such as nitrogen mustard (1.1 mg/kg (p. o., rat)) or carboquone (5, 43 mg/kg (i. p., mouse)) was observed. These studies strongly suggest that the localized distribution of CA 102 within the enterohepatic circulation reduced the systemic toxicity and increased the selective cytotoxicity against tumor cells in the liver.

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