Recently, an attempt to target anticancer agents to the tumor cells by controlling their in vivo disposition behavior has attracted great interest in cancer chemotherapy. However, these approaches including monoclonal antibody conjugate can not achieve sufficiently effective targeting by the systemic administration due to ; (1) predominant uptake by the reticuloendothelial system such as the liver before arriving at the target site, (2) difficulty in escaping from the blood space to the interstices of the tumor, (3) lack of sufficient affinity to the tumor cell surface, (4) low efficiency in cellular internalization and drug release. In this paper, I will show our systematic approach to manage these problems in a design of immuno-conjugate of mitomycin C. Pharmacokinetic analysis of systemic disposition at a whole body level, local disposition in an organ perfusion system, and cellular association of the conjugates are discussed in relation to their physicochemical and biological characteristics. Based on these informations, we have designed macromolecular prodrugs of mitomycin C with therapeutic success. Possible application of drug delivery systems in a future cancer chemotherapy is also discussed.

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Liposomes expressing external antibody specific for Candia albicans and encapsulating amphotericin B were studied. Fluorescent microscopy indicated that the antibody showed specificity for the yeast cells of C. albicans and it was modified by papain to antibody fragments (Fab'). Fab' fragments were conjugated with egg phosphatidylcholine liposomes coated with pullulan derivatives bearing maleimide group and twenty-two Fab' fragments were connected with one liposome in this study. Candida albicans phagocytized by macrophage was mixed with free amphotericin B (FAMB), liposome-encapsulated amphotericin B (LAMB), and amphotericin B liposomes bearing antibody (LAMB-Ab), FAMB was the most effective but LAMB and LAMB-Ab showed similar effects against C. albicans. Candida albicans was mixed with FAMB or LAMB or LAMB-Ab and added to macrophages. FAMB showed the most efficient killing of the yeast cells and LAMB-Ab was more effective than LAMB but there was no significant difference between LAMB and LAMB-Ab. To investigate the efficacy of LAMB and LAMB-Ab in mice with disseminated candidiasis, the number of the fungi in lungs, liver, spleen and kidneys were examined. However there was no significant difference between LAMB and LAMB-Ab.

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Pullulan-coated liposomes conjugated with monoclonal antibody (immunoliposomes) have been developed. The usefulness of the immunoliposomesencapsulated adriamycin (MoAb-Lipo [ADR]) was examined on targeting cancer chemotherapy in an animal model. The mouse monoclonal IgM antibody (CSLEX 1) by immunization with human stomach cancer was used. MoAb-Lipo [ADR] was compaired with pullulan-coated liposomesencapsulated adriamycin without CSLEX 1 antibody and ADR alone. There was no differences in cytotoxic activity in vitro against human lung cancer cell line (PC-9), reacting with CSLEX 1, among them. However, MoAb - Lipo [ADR] inhibited the growth of the implanted PC-9 tumor in vivo more strongly than the others. The ADR concentration in tumor was higher at 30 min to 8 hr after the administration in MoAb-Lipo [ADR] than in the others. In the heart, it was lower in liposomal ADR than in ADR alone, which was a significant benefit. These results demonstrated that MoAb-Lipo [ADR] was an ideal drug carrier on targeting cancer chemotherapy.

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We have tried chemoembolization therapy of hepatic artery for hepatic tumor-bearing rats using temperature-sensitive liposome containing adriamycin with local hyperthermia. In this report, first, the formation of embolus of liposome with about 1 μm diameter injected into hepatic artery was confirmed using selective angiography by soft X-ray imaging. The embolization of hepatic artery continued over 2 days. Next, the site of embolus was investigated using a stereoscopic microscope with liposomes containing a dye, methylene blue. The embolus was mostly in hepatic artery. In some cases, the embolus distributed in sinusoid at hepatic lobule. A lack of blood stream at places in the hepatic lobule was also observed.

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Temperature-sensitive liposomes containing doxorubicin (DXR-TSL (pH)) composed of DPPC (Tc = 41°C)/DSPC (Tc = 54°C) (9 : 1 in molar ratio) were prepared by pH gradient method and evaluated concerning tumor uptake of DXR. Colon 26 tumor cells were inoculated in hind foot of BALB/c mice and local hyperthermia (42°C, 20 min) was done at tumor site. The pH gradient method was employed to raise the encapsulation rate of DXR into temperaturesensitive liposomes. This preparation resulted in the remarkably high encapsulation rate with 98%. The tumor uptake of DXR with the combination of DXR-TSL (pH) and the local hyperthermia were 3 times greater than those of free DXR. The higher accumulation of DXR in liver and spleen was observed. In these accumulation, the distribution of liposome rather than released DXR was contributed mainly. Present data indicated that DXR-TSL (pH) have some advantages for the antitumor effect, since DXR content per liposome is high and the controlled release of DXR from liposomes with hyperthermia is possible.

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A milk fat globule membrane (MFGM), which is the cell membrane derived from lactating mammary-gland cells, keeps fat globules stable in emulsion. The emulsifiability of MFGM is as strong as HCO60 and polysorbate 80, MFGM is expected to be a drug carrier. We have studied the intestinal absorption of MFGM-insulin emulsion in D. M. rats induced by streptozotocin. MFGM-insulin emulsion decreased blood glucose levels and increased serum insulin levels significantly. In the study of the intestinal lymphatic, MFGM-insulin emulsion significantly increased lymphatic insulin levels, as well. Compared with the lymph-borne and hematogenous absorption of insulin, the lymph-borne absorption was 3∼4 times more than the hematogenous absorption. These findings suggest that MFGM could be lymphotropic drug carrier on the oral administration.

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Shirasu porous glass particles (SPG) having a lot of pores of 500Å in diameter were prepared as a new drug carrier for cancer chemotherapy, and their chemical and biological features were studied. The particles are composed of SiO₂, Al₂O₃ and Bl₂O₃, and their mean diameter is 10μm. Bleomycin(BLM) was used as an anti-cancer agent. SPG and BLM were shaken in saline of thermoincubator for 1 hour so that SPG could effectively adsorb BLM (SPG-BLM). About 40% of BLM was adsorbed to SPG at 37°C. On the other hand, the desorption of BLM from SPG-BLM was occurred in keeping the sigmoid relationship with the degree of dilution. The desorption rate was 82%, when SPG-BLM was diluted 8 times in saline. While ELM was immediately solved in saline, only about 30% of BLM was released into saline from SPG-BLM through the dialytic membrane at room temperature during 14 days. The biological activity of BLM was measured by thin agar plate bioassay using Bacillus subtilis PCL-219. The higher the concentration of SPG-BLM, the more significant the activity of BLM. And the activity became marked with the passage of time. In an acute toxicity experiment, no remarkable side-effects were observed both pharmacologically and histopathologically. Consequently, it was suggested that SPG are useful as a drug carrier and that administration of SPG-BLM is an effective anti-cancer modality especially in local chemotherapy.

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Polymeric durg delivery systems that allow the application of substances to a localized region for specified periods of time have been developed. After endothelial injury using a balloon catheter technique in 10 rats, the adventitial surface of the carotid artery was exposed to the polymer polyvinyl alcohol (PVA) containing heparin (heparin/PVA) and was compared with exposure to PVA alone in the contralateral(control) vessel. Morphometric analysis of the cross-sectional thrombus : lumen ratio in 10 rats 90 minutes after endothelial injury showed a significant reduction(P<0.005) in thrombus size for treated vessels (4.1±9.6%) compared with control vessels(60.2±25.8%) in the study for intravascular thrombosis. Segmental endothelial desquamation of the common carotid artery in 30 rats produced consistent proliferation of intimal smooth muscle cells from 5 to 20 days after injury. 15 animals were treated with heparin/PVA and PVA alone applied to 15 control rats in a similar fashion as described above. At all time periods, there was a significant reduction in intimal cross sectional area in heparin/PVA-treated vessels compared to control vessels. In the both studies for intravascular thrombosis and intimal proliferation, femoral venous prothrombin time and partial thromboplastin time were unchanged in heparin/PVA-treated animals compared to controls.

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Eudragit L and/or RS microcapsules contained 5-aminosalicylic acid (5-ASA) were prepared. The microcapsules having pariticle sizes in the region of 53-150 μm were dispersed into Witepsol S-55 which has been known to be distributed uniformly from rectum to colon after rectal administration. In in vivo evaluation using rats, the plasma concentration-time profiles of 5-ASA obtained after rectal administrations of suppositories dispersing microcapsules showed clearly sustainedreleasing and maintained 5-ASA concentration at almost constant levels 12h after administration. The microcapsules containing 5-ASA in suppositories were widely distributed from upper rectum to colon and higher residual percentages of 5-ASA in large intestinal lumens were obtained compared with the conventional suppositories contained 5-ASA powder.

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