5'-phosphatidyl-FURs, with the same backbone structure as that of natural phospholipids, in which a polar-head group of usual phospholipids is replaced by a cytotoxic nucleosides, 5-fluorouridine(FUR), were designed to be potent antitumor agents. 5'-phosphatidyl-FURs were synthesized by transphosphatidylation catalyzed by phospholipase D from phosphatidylcholines and FUR, and showed greater antitumor activity than FUR. We demonstrated that a 5'-phosphatidyl-FUR given orally was absorbed via a specific pathway for natural phospholipids, namely deacylation-reacylation cycle, to be transported highly selectively to lymph in rats, which suggested effective use of antitumor pseudo-phospholipids, in targeting chemotherapy of metastases of tumors. In fact, 5'-phosphatidyl-FUR showed significant antitumor activity both against P388 leukemia metastasized to the lymph node and P815 mastocytoma metastasized to the lever in mice. These results suggested that the pseudo-phospholipids could be recognized as phospholipids by the body. This methodology of DDS would be applicable for various antitumor agents as well as other biologically active compounds.

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Various kinds of the neoglycolipids, composed of N-acethylgalactosamine(GalNAc), a spacer arm and a lipid, were synthesized to modify the surface of liposomes and to investigate the distribution of the liposomes. The neoglycolipids, having octamethylene as a spacer arm, are only slightly soluble in various kind of solvents. However, by using tricthyleneglycol as a spacer arm, the solubility of the neoglycolipid was greatly improved without loss of the affinity towards hepatocyte in vivo. Liposomes modified with the neoglycolipid, which contained the branched lipid as an anchor, showed remarkable accumulation in the liver. However, liposomes modified with the straight chain lipid as an anchor showed the same accumulation in the liver as the control liposomes. The accumulation depends on the structure of the anchor part of the neoglycolipids. We synthesized the neoglycolipid, which contained three GalNAc residue, branched with L-glutamyl-L-glutamic acid (clustered GalNAc derivative). The clustered GalNAc derivative showed higher affinity towards hepatocyte than unclustered GalNAc derivative in vitro. The liposomes modified with the clustered GaINAc derivative were disappeared faster from plasma and accumulated more in the liver than the control liposomes after intravenous injection to rats. Although the accumulation of clustered GalNAc derivative coated liposomes in the liver was the same extent as the accumulation of non clustered GalNAc derivative modified liposomes. So cluster effect was not observed in in vivo examination.

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The extent of systemic availability of morphine after the nasal administration of morphine hydrochloride in solution was much greater than those when the opioid was given orally in solution and rectally in suppository in rats. The ratio of area under the plasma level-time curve of intact morphine to the main metabolite, morphine-3-glucuronide for the nasal administration was about twice those for the oral and rectal administrations and almost equivalent to that for the intravenous administration. Furthermore, higher levels of morphine in the cerebrospinal fluid were attained after the nasal administration compared with the oral and rectal routes. The nasal administration of morphine produced a dose-dependent analgesic response, as measured by the hot-plate method. The efficacy of morphine to block the hot-plate response increased in the order : oral < nasal < subcutaneous route. The scanning electron microscopic observations and membrane permeability studies using a transport marker, 6-carboxyfluorescein revealed that morphine neither induced noticeable changes in surface morphology of the nasal mucosa nor affected the nasal membrane permeability to the transport marker. Dimethyl-β-cyclodextrin significantly enhanced the rate of nasal absorption of morphine by facilitating the nasal epithelial permeability and consequently increased the entry of the opioid into the cerebrospinal fluid. In contrast, 2-hydroxypropyl-γ-cyclodextrin sustained the plasma levels of morphine, probably through the formation of a complex that was less permeable through membranes. The present results suggest that the nasal cavity is a potential route of administration for morphine to bypass first-pass metabolism and is able to deliver the opioid more effectively into the central nervous system. A proper use of the cyclodextrin derivatives in nasal morphine preparations may provide adequate analgesia for both acute and chronic pain states, thus offering an improvement in patient comfort.

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One of the “dreams” of cancer treatment is missile therapy targeted specifically to cancer tissues. At first, monoclonal antibodies were expected to play primary roles in this therapy and were studied globally at a number of institutions. However, the practical use of monoclonal antibodies is hampered by their poor accumulation in tumor tissues and side effects such as the human antigen-murine antibody reaction (HAMA) phenomenon. Porphyrin derivatives are low-molecular-weight agents that accumulate in tumor tissues and have recently attracted much attention as possible substitutes for monoclonal antibodies We have synthesized about 750 porphyrin-related derivatives since 1980, when we first became interested in the tumor tissue accumulating property of porphyrins, and have studied them in many respects. The mechanisms of tumor tissue accumulation of porphyrins as we speculate at present are followings ; Important factors are the strong affinity of porphyrins to proteins because of their high π electron contents and the amphipathicity to water and oil due to the stacking phenomenon. As for the tumor tissue, active endocytosis associated with enhancement of LDL and transferrin receptor activities and the immaturity or lack of lymphatic tissues in tumor are important factors. The increased permeability of tumor vessels, which has been discussed for years, is also considered to be a factor in tumor tissue accumulation of porphyrins. In this issue, recent knowledge about the mechanism of accumulation of porphyrins in the tumor tissues and the prospects of their application to the diagnosis and treatment of cancer are discussed.

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筆者らは，後腹膜リンパ節転移に対し，OK-432を局注し，リンパ指向性を持たせ，局注した範囲を透視下で知るのと同時に徐放性を持たせることを検討している．そこで，OK-432とリピオドールとの混合液の外観と顕微鏡下での相分離の過程と，エマジョンの状態を経時的に観察した．OK-432を生理食塩水で混和，リピオドールと懸濁したが，安定したエマルジョンは得られなかった．(1)そこで，非イオン性造影剤であるイオパミロン300を生理食塩水の代わりに用いたが，混合直後から水相の合一が観察され，3時間後にはすでに相分離を起こしていることが外観の観察から確認された．(2)また水相と油相の比重差を軽減した処方でのエマルジョンでは，合一の速度は抑制できなかったものの，沈降，浮上の要因は解消された．しかし，(1)と同様の経過をとり，より安定したエマルジョンは得られなかった．このように沈降と浮上による合一が避けられたものの，相分離が進行するのは水相同士の接触による合一の確率が高いというところに起因すると推測し，さらに水相と油相の混合体積比をかえた実験を試みた．(3)比重差を軽減した水相の体積を従来の半分にまで下げ，水相:油相が3:1のところを6:1にし，エマルジョンを調製したところ，かなりの安定化傾向が得られた．これらの結果から，この系では安定したエマルジョンの状態が保持されているものと考えられた．筆者らは後腹膜リンパ節転移に対し，OK-432を局注する処方として，(1)，(2)，(3)の処方を考えた．(3)のような，比重だけでなく体積比も考慮した処方は，筆者らの目的に適した処方であると考える．

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Recently, there is increasing interest in the targeting of peptide and protein drugs to the colon because of the low activity of proteolytic enzymes in the colon. Therefore, many dosage forms such as a time controlled-release dosage form and a pH-sensitive coating dosage form were examined for the specific drug delivery to the colon. However, these approaches have recently been shown to lack site specificity, since the variability of pH and small intestinal transit time of these dosage forms were observed. On the other hand, chitosan, which is one of the polysaccharides widely in nature, is known to be specifically degraded by microorganisms distributed in the colon. In this study, therefore, we prepared chitosan capsules containing insulin and examined the effectiveness of these capsules to colon-specific delivery of insulin. The chitosan capsules containing CF or insulin were obtained from Aicello Chemical Co., Ltd. (Toyohashi, Japan). The mean diameter and weight of these capsules were 3.5 × 1.6 mm and 1.2-1.5 mg, respectively. The surface of these capsules was coated with hydroxypropyl methylcellulose phthalate as enteric coating material. The release studies of drug from the chitosan capsules were carried out using Japan Pharmacopoeia(J. P.) rotating basket method. 5(6)-Carboxyfluorescein (CF), which was encapsulated in the chitosan capsules was used as a water soluble model compound. No release of CF from the capsules was observed in liquid 1 as an artificial gastric juice (pH1) and liquid 2 as an artificial intestinal juice (pH7). However, the release of CF was markedly increased in the presence of rat cecal contents. These findings suggested that the chitosan capsules were degraded by the microorganisms in rat cecal contents. The effectiveness of the chitosan capsules to the colon specific delivery of insulin was investigated by an in vivo absorption experiment. A marked decrease in plasma glucose levels was observed following oral administration of these capsules containing 20 IU insulin and Na-glycocholate, as compared with the capsules containing lactose or insulin only. In addition, the chitosan capsules containing insulin and Na-glycocholate were more effective for reducing the plasma glucose levels than the gelatin capsules containing the same components. Thus, this capsule may be a useful carrier for colon-specific delivery of peptides including insulin.

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We have tried the hepatic artery chemoembolization therapy for hepatic tumor-bearing rats using liposomes containing adriamycin as a material for embolization and found the enhanced therapeutic effect against W256 carcinosarcoma-implanted rats. In this report, we discussed the therapeutic effect against the primary hepatic tumor induced by dietylnitrosamine. Any embolization with liposomes consisting of dipalmitoyl-phosphatidylcholine alone was not observed on the primary liver cancer-bearing rats. It is contrasted with W256 implanted model. Polysaccharide modified liposomes made it possible to form embolization. Especially, chondroitin sulfate-modified liposomes showed the high accumulative property of entrapped adriamycin into the hepatic tumor of the rats and significantly increased their life time.

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The physicochemical factors (the diffusion and partition coefficients) which control the drug transport in the vitreous body, retina, lens and posterior chamber, were measured in the in vitro experiment using isolated rabbit tissues. The diffusion coefficient in vitreous body decreased with increasing the molecular weight of drugs to the exponent of 0.34. The drugs whose molecular weight is greater than about 600 hardly penetrated across the retina/sclera membrane. The in vivo elimination profile of ganciclovir from the vitreous body following the membrane-moderated intravitreal delivery device agreed with the profiles calculated from the pharmacokinetic model, together with the model parameters determined from the present in vitro experiments.

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