Molecular design of DDS was discussed focusing on the polymer utilization. The polymeric materials used for DDS were classified into biodegradable and non-biodegradable. Further, the biodegradable polymers were divided into naturally occurring and synthetic. Current topics on delivery systems of protein drugs, oral drug delivery, and slow release of anticancer drugs using biodegradable microspheres were briefly described. In addition, the fundamentals of active and passive targeting were summarized. Importance of studies on pharmacokinetics of injected polymers was stressed and recent results in this field were presented.

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Blood is known to be the main transport route of most drugs because of the much greater flow rate of the blood stream than that of the lymphatics. The lymphatic transport of drugs, however, is noteworthy, because the lymphatic route is important for many chemicals ; namely as an essential route for nutrient lipids and a route to avoid the first pass effect of the liver for drugs which are absorbed from the gastrointestinal tract and the necessity to deliver anticancer agents into the lymphatic system of patients suffering from the cancer. It follows that in tumor metastasis, the lymphatic pathway is a major route and a lymphotropic transport of antitumor drugs is to be of great significance for cancer chemotherapy. In this paper, fundamentals of lymphatic transport of chemicals, development of lymphotropic drug delivery systems and their application to therapy are described.

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Therapeutic applications of prolonged controlled release parenteral microcapsule systems using biodegradable polymer were discussed. The microcapsule system has advantages as follows : the system can be easily injected with a suspending vehicle and a conventional syringe ; it is not necessary to take the system out of the injection site after the release of all the drug, permitting this system to be injected into the same site chronically ; in many cases, smaller doses than those required in the cases of injecting aqueous solutions are expected to be sufficient with increased pharmacological effects when its system is used. Recently, applications for a highly potent LHRH agonist were reported. The system consisted of a biodegradable polymer, copoly (lactic/glycolic) acid (PLGA), containing a highly potent LHRH agonist termed leuprolide acetate released the drug for one month at a pseudo zero order kinetics. The microcapsules were applied clinically for treatment of prostate cancer, resulting remarkably that the microcapsules effectively reduced the dose of the drug required to up to one-fourth of that needed when an aqueous solution is injected daily. This system provides an ideal delivery of water soluble peptide hormone. Further, limits of this system to apply a drug are discussed.

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Monoclonal antibody A7 against human colon cancer was conjugated with mitomycin C-dextran conjugate having anionic charge (MMCDan) through thioether bond in exchange for disulfide bond, because the disulfide bond in the immunoconjugate is more subject to cleavage in vivo than the thioether bond. The coupling was done using the bifunctional reagents succinimidyl 6-maleimidohexanoate (EMCS) for amino groups introduced MMCDan and S-acetylmercaptosuccinic anhydride (SAMSA)for antibody instead of using succinimidyl 3-(2-pyridyldithio)propionate (SPDP). This A7-MMCD conjugated with thioether bond, having MMC prodrug properties, released active MMC with a half life of 26.3 h and almost fully retained its antibody activity. The cytotoxicity of A7-MMCD against the human colon cancer cell line, SW1116 was comparable to free MMC and was also reduced by the addition of excess A7, which indicated that the cytotoxicity was mediated through its antigen-antibody binding. The A7-MMCD conjugated with thioether bond is expected to be more stable in vivo and to exhibit greater therapeutic effects than one conjugated with disulfide bond prepared previously.

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Water soluble aclalubicin hydrochloride(ACR, Aclacinone^®, Yamanouchi Pharmaceutical Comp. Japan) was dissolued into Lipiodol Ultra-Fluid^®(Kodama Co. Ltd. Japan) with an addition of an equivalent amount of 7% sodium bicarbonate (Meylon^®, Otuska Pharm. Co. Ltd. Japan). A maximum concentration of ACR in LPD reached to approximately 20 mg/ml. Release of ACR from ACR/LPD solution was documented for more than 6 weeks period. Intraarterial infusion of ACR/LPD (1.5 mg/0.1 ml/kg) reduced tumor growth significantly(P<0.01-0.05)in rabbit VX-2 hepatoma model comparing to groups they received ACR/H₂ O solution (ACR 1 mg/kg, 1.5 mg/kg), LPD alone(0.1 ml/kg), and ACR/LPD (1.0 mg/0.1 mg/kg). These results suggest that the ACR/LPD solution with 7% sodium bicarbonate may be an active agent for intraarterial targeting chemotherapy which has delayed releasing of ACR.

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Idiotype network systems are supposed to play important roles in regulation of the immune response. We applied anti-idiotypic(Id)monoclonal antibodies (MoAbs) to tumor associated antigen system to analyze idiotype networks and the internal image of antigen. Anti-Id MoAbs were developed to anti-CEA MoAb MA208 which reacted with peptide of CEA. One of the and-Id MoAbs, M7-625 could induce anti-anti-Id antibodies which reacted with antigen-CEA, suggesting that MoAb M7-625 serologically had the internal image of antigen. In order to confirm this point, the cloning experiment of M7-625 variable region was done. It showed that amino acid sequences of coplementary determining region (CDR) 2 and 3 of MoAb M7-625 heavy chain had the homology to those of CEA domain III. Furthermore, internal image-bearing anti-Id MoAb in ganglioside GM3 antigen system showed the vaccine effect against syngeneic B16 melanoma in C57/BL black mouse. These results suggest that internal image-bearing and-Id MoAbs are useful tools for cancer therapy.

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Systemic delivery of mitomycin C (MMC) was studied in 16 patients administrated mean dose of 19.7 mg of microencapsulated MMC (MMC-mc) by an intra-arterial infusion : 7 renal arterial infusions, 9 hypogastric arterial infusions. Pharmacokinetic data revealed a lower blood MMC availability for the hypogastric artery than for the renal artery ; this was attributed to differences in the blood flow rates at these two target sites. Direct comparison of systemic MMC level was possible for one patient, who serially received IA renal MMC-mc (10 mg) and IA renal MMC (10 mg in standardform). Peak concentration was much higher for MMC than that for MMC-mc. Hematological data of peripheral blood was influenced by embolization and cytotoxic activity of MMC. Bioavailability observed for these patients indicate, a quantitative local improvement in exposure to the drug and correlates well with the low incidence of systemic side effects noted in preliminary clinical studies.

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We have already conducted local therapy by slowly releasing anticancer composite to malignant brain tumors. We administed either ACNU pellet or 5Fu pellet at the time of the operation or under CT guided in treating of 81 cases of malignant brain tumor. From 1 to 10 pellets containing 10 mg-20 mg of ACNU of from 1-6 pellets containing 5 mg-20 mg of 5Fu were administered. In ACNU cases, the response of the tumor tissue to local therapy was not so strong and no peripheral edemas was observed on CT scan. In the 5Fu pellets cases, a severe brain edema was seen in and around the pellet from the 7th to 21st days after implantation of pellet. This edema gradually improved and showed low density only around the lesion. It is thought that this is due to the occurence of leucoencephalopathy of cause of 5Fu. Sufficient histological studies have not yet been carried out. But in one case who was reoperation on the 10th day after pellet implantation, histological examination revealed marked tissue necrosis and no remaining tumor cells were seen. Thus the tissue response to 5Fu is extremely strong. 5Fu-pellet shows a stronger cytotoxic effect and greater degree of tissue infiltration than ACNU. Copolymers of lactic acid and valerolactone with a number-average molecular weight of 1500-2600 were developed as biodegradable carriers for drug delivery. When CDDP-lactone polymer was implanted in the brain of rat, histologically, the brain tissue is markedly changed. The area of necrosis and response of connective tissue were seen around the implantation site from 5th day to 20th days.

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Poly(L-lactic acid)microspheres containing tetracycline (TC-PLA-MS) were experimentally produced for periodontal therapy, and the sustained release of tetracycline(TC) in this preparation was examined. TC-PLA-MS were prepared by the oil-in-oil emulsion method(average diameter of MS : 10∼20 μ ; TC : 5, 10, 20% loading ; MW : 3700, 5400, 8700). The in vitro test of TC release was conducted using the UV method, while sustained release in vivo was determined by bioassay using S. aureus as verification bacteria. For the latter test, TC-PLA-MS(TC 10% loading ; MW : 5400)were prepared with hydrophilicpetrolatum (VH) or 3% atelocollagen solution(AC)as the base to yield gel, and injected into periodontal pockets. The test was performed 1, 2, 3, 4, 7, 10 and 14 days after administration. Sites treated by irrigation with TC solution (50 mg/ml, 200 mg/ml) were used as positive controls. In the in vitro test of TC release, about 50% of TC was released by day 1 after administration, and the release tended to be suppressed thereafter. In testing of sustained release in vivo percentage occurrence of the inhibition zone was decreased to about 50% by 2 or 3 days after administration, and was maintained at the same level until day 14. TC concentration remained almost stable (30∼60 μg/ml) after day 2. There was no noticeable difference in the pattern of sustained TC release by different bases(VH and AC). In the irrigation-tereated group, the inhibition zone appeared until day 4, and TC concentration decreased daily.

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Phenol red and FITC-dextrans with various molecular weight were chosen as model drugs and the absorption promoters used in this study were Na-glycocholate, Na-salicylate, ethylendiaminetetraacetic acid (EDTA) and Na-caprate, all at a concentration of 1%. Of the absorption promoters, Na-glycocholate and Na-caprate appeared to be more effective to enhance the nasal and pulmonary absorption of these drugs than Na-salicylate and EDTA : For nasal absorption, Na-glycocholate and Na-caprate showed the highest promoting effect to drug with molecular weight 4000, while the maximal effect of these promoters was observed in the pulmonary absorption of drug with molecular weight 10000. EDTA showed the greatest promoting potency to drug with molecular weight 4000 in both routes, although its promoting potency for nasal absorption was more effective than that for pulmonary absorption. In contrast, Na-salicylate did not affect the absorption of drugs with various molecular weight in both routes. In conclusion, effect of absorption promoters on nasal and pulmonary absorption of drugs was molecular weight dependent. These findings give us useful basic information to select the optimal absorption promoters for peptide and protein delivery.

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Antitumor effects of ethyl oleate (EO), Lipiodol Ultra-Fluide^® (LP) and viscous ethyl oleate (VEO) containing cis-diamminedichloro platinum (II) (CDDP) on the tumor-bearing animals were investigated. The in vitro CDDP release from EO and LP was fast and the total CDDP was released within 24 h. In contrast, CDDP release from VEO was very slow. When these oily drug carriers were infused into the proper artery of the liver implanted with VX-2 tumor in rabbits, the rank order of the accumulation of CDDP in the tumor site was VEO > LP > EO. However, the inhibition effect of these oily drug carriers on the tumor growth was almost the same. Next, controlled drug release property of the VEO was evaluated by addition of non-ionic surfactants (Tween 80, Span 20 and 80) using the AH 272 ascites in rats. The in vitro CDDP release from the VEO containing the surfactants was faster than that without the surfactants (the extent of suppress was Span 80 > Span 20 > Tween 80). The mean survival (T/C%) of EO-, LP-, VEO containing Tween 80, Span 20 or Span 80-treated groups was 164.5, 179.4, 166.7, 298. 6 or 475.4, respectively. These results suggested that VEO containing non-ionic surfactants was very useful as a bifunctional drug carrier with abilities of “targeting” and “controlled release” for intra-arterial infusion therapy.

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