We have developed the coating of liposomes with a cell specific polysaccharide. Carbohydrates play a very important role in biological recognition system. In this study, galactosamin(1), 1-amino-galactose(2), 1-amino-mannose(3), 1-amino-glu-cose(4)was selected and partly replaced to be an effective sensory device on naturally occurring polysaccharide such as pullulan. The polysaccharide-coated liposomes become significantly stable both physicochemically and biochemically and also cell recognizable. Recognizabilities of the poly-saccharide-coated liposomes were confirmed by specific lectin-induced aggregation, cell-liposome interaction, and tissue distribution. Liposomes coated with pullulan derivatives(1-3)were effectively endocytosed by human neutrophils and monocytes, while liposomes coated with pullulan derivative(4) inhibited the endocytosis. When galactosamin-modified pullulan-coated liposome was intravenously administrated into mice, liver uptake increased compared with the simple pullulan-coated liposome. These findings suggest that terminal sugars of modified polysaccharides act as a potentially valuable sensory device of drug delivery system.

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New intravesical instillation therapy was performed in eleven patients with urinary fungi infection. Anti-fungal agent(HPC-Am)was made by emulsing 50 mg of amphotericin B(Am)in 15 ml hydroxypropylcellulosum(HPC). HPC-Am was given intravesically through a urethral catheter and retained for approximate an hour. A clinical relief of manifestation with absence of fugi was subsequently obtained in 9 out of 11 patients. After intravesical administration just one time, effective urinary concentration of Am against the fungi was continued for the longast period of 6 consecutive days. There was no adverse reaction of this therpy. These findings suggest that HPC-Am therapy shows more clinical effect rather than conventional Am instillation.

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Seven hundred and fifty nine patients with malignant tumors were treated by intra-arterial infusion with microencapsulated anticancer drugs from 1978 to 1986. Mean age of the patients was 60.3 yrs(13-88). Fifty seven percents of patients had stage 4 tumor and 41%were grade 3-4 in performans status. The target organs subjected to the treatment were liver(310), kidney(177), bladder(100), prostate(41), lung(39), pelvic organs(13), bone(4)and the others (75). Median doses of drugs in microcapsules were 20 mg for MMC, 40 mg for PEP and 60 mg for CDDP. Of 455 measurable tumors, 113(25%)showed a substantial reduction of greater than 50%. In 508 evaluable patients, side effects frequently recognized were fever(57%)and local pain(50%)shortly after the treatment. However, these side effects were generally mild and temporary. Gluteal skin ulcer occured in 33 patients(21%)who underwent hypogastric arterial infusion, but improved within a few months. Only one patient died of treatment-related cause. These results suggested that microcapsule therapy can be successfully applied to a variety of tumors with low morbidity and low mortality, and also can be combined with other treatments in multidisciplinary therapy.

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For the purpose of enhancing selective transfer of anticancer drug into the tumor and the regional lymphnode in esophageal cancer chemotherapy, we aimed at the administration of the anticancer drug into the lumen of the esophagus. We have reported the effectiveness of using lipid-surfactant mixed micelles(MM) as an absorption promotor and a dextran sulfate(DS)as a lymphotropic carrier. In this study, we observed the antitumor effect of this system. An experimental model of esophageal cancer was made by implanting VX2 carcinoma endoscopically into the esophageal wall of rabbits. We treated these rabbits with distilled water alone, peplomycin(PEP) with distilled water, PEP with MM, and PEP·DS ionic complex with MM, respectively. The antitumor effect of each group was evaluated by the histological findings and the weight of metastatic lymphnodes. The administration of PEP·DS complex with MM showed the good antitumor effect not only in the primary tumor of esophagus but also in the metastatic lymphnodes. Consequently, it was recognized that the antitumor effect of PEP was enhanced by using MM together with DS and we expect the clinical application of this system.

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The recent studies of cancer therapies toward drug targeting to tumor cells are reviewed. There are several problems in the approach of drugs to the tumor cells after administration such as the trans-port through normal tissues, the selectivity of tumor tissue, and the permeability through the membrane of the tumor cells. Many biocompatible materials have been attempted to be used to overcome these problems. Microspheres of proteins, lipoidal particles(liposomes and emulsions), and biodegradable artificial polymers are used as carriers to study passive targeting in body, and also membrane active materials in lipoidal substances are used to solve the insensitivity and the tolerance of tumor cells to antitumor drugs. Also the formulation design of drug using poly(lactic acid)microspheres is presented for the example of lymph targeting and controlled release to prevent tumor metastasis.

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Activated carbon particles adsorbing anticancer drugs release the anticancer components at designated levels for a long period at the target tissues, while distribute at a low level to the whole body. Moreover, the particles target the car-cinomatous tumor because of the tendency to adhere the tumor surface. In animal experiments, relatively large particles of activated carbon adsor-bing mitomycin C(MMC-CH)decreased the toxiaty into 18.5%, and its therapeutic efficacy on carcinomatous effusion(LD₅₀/ED₅₀)was 3 times, as compared with those in mitomycin C aqueous solution. Intraperitoneal MMC-CH extended the survival time of rabbits with peritoneal carcinomatosis longer than mitomycin C aqueous solution did. In clinical trials, 51 of 81 patients with carcinomatous effusion(63%)responded well to the MMC-CH therapy. The survival time of the patients with gastric cancer invading into the peritoneum was increased by intraoperative MMC-CH therapy statistically significantry higer than that of historical control group. Very small activated carbon particles adsorbing peplomycin(PEP-CH) showed superior therapeutic effects on lymphatic metastases and a low pulmonary toxicity, as compared with peplomycin aqueous solution. Seven inoperative patients underwent local injection of PEP-CH against esophagael cancer. The response rate was 86% and the mean survival time was 14.3 months.

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I have found that the arterially injected lipid lymphographic agent, lipiodol ultrafluid, remaines selectively in hepatocellular carcinoma(HCC)and other malignant solid tumors. Using this characteristic nature of lipiodol, targeting cancer chemotherapy was achieved. It was shown that anticancer drug had to he dissolved in lipiodol and diffused out gradually from the agent in order to achieve targeting cancer chemotherapy. SMANCS/lipiodol, mitomycin C/lipiodol, aclarubicin/lipiodol and doxorubicin/lipiodol were successfully developed. Clinically, these oily anticancer agents were administered to 281 patients with HCC and 98 patients with metastatic liver cancer. Remarkable anticancer activities were proved based on decreased in tumor marker(AFP and CEA level decreased in 92%and 73%of the cases, respectively)and reduction in tumor size(in 94% of the patients with HCC and 47% of the cases with metastatec liver cancer). It was proved that survival period of the patients with unresectable tumors was definately prolonged (one year and two years survival rates of HCC and metastatic liver cancer were 64%, 26% and 58%, 21% respectively). Neither hernatosuppression nor any side effects due to anticancer drugs were observed.

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Monoclonal antibody A7, from a mouse splenocyte immunized against human colon cancer, was used as a drug carrier for colon cancer. Neocarzinostatin(NCS)was bound covalently to A7 to form A7-NCS. The A7-NCS, which exhibited a strong in vitro and in vivo antitumor activity, was applied as a clinical trial for forty-one patients with colorectal cancer. Of the eight patients with liver metastasis, five showed some improvement such as tumor reduction on computed tomography and pain relief. Patients recieving A7-NCS did not experience serious adverse effects. Mitomycin C-dextran conjugate with anionic charge(MMC-Dan)was bound to A7 in order to bind large amount of MMC. Amino groups-introduced MMC-Dan was linked to A7 using SPDP. The molar binding ratio(IgG : dextran : MMC)in the conjugate(A7-MMCD)was estimated to be 1 : 1.2 : 40. Under physiological conditions, MMC was released with a half life of about 29 hours. A competitive binding assay revealed that the A7-MMCD retained almost full antibody activity. The in vitro cytotoxic effect on SW1116 cells was 10 times stronger than MMC-Dan. ¹¹¹In labeled A7-MMCD accumulated in SW1116 about 5 times greater degree than in sarcoma 180 in mice. The A7-MMCD showed a strong antitumor effect on colon cancer transplanted into nude mice.

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