This article is a brief review and analysis of the past, present, and future of the field of drug delivery. It covers the golden age of pharmaceutical sciences and product development, followed by the incorporation of biological and clinical information into more and more sharply defined strategies for drug delivery and the formation of specialty drug delivery companies. Finally, some thoughts on the future of drug delivery sciences and delivery products in the changing dynamics of health care environment and the development of greater and closer working relationship among the discovery scientists, clinical scientists, and delivery scientists are mentioned.

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The current status of the passive targeting by the newly developed polyethyleneglycol coated liposome (PEG-liposome) was described in this review. Liposomes have demonstrated considerable promise as a carrier for the delivery of drugs in vivo. However, one of the drawback is that ordinary liposomes intravenously injected into animals are rapidly removed from the blood circulation by uptake primarily in the cells of reticuloendothelial system (RES). It has been found that PEG-liposome are not readily taken up by the macrophages in the RES and hence stay in the circulation for a relatively long period of time. PEG-liposome is called STEALTH^® liposome. Pharmacokinetic analysis and therapeutic studies with tumor bearing mice revealed that PEG-liposomes with an average diameter of 100-200 nm were accumulated efficiently in tumor tissue. Due to the capillary permeability of the endothelial barrier in newly vascularized tumors is significantly greater than that of normal tissues, PEG-liposomes could extravasate from blood circulation to tumor tissue. Results from clinical studies with doxorubicin encapsulated into PEG-liposomes (DOXIL^®) in AIDS-related Kaposi's sarcoma revealed an increased therapeutic efficacy compared to free-drug. PEG-liposomes offer the development of immunoliposomes with both long survival times in circulation and target recognition being retained in vivo. A new type of long-circulating immunoliposome, which was PEG-immunoliposome attached antibody at the distal end of PEG chain, so called the pendant type immunoliposome, was designed. For targeting to the solid tumor tissue, Fab' fragment of 21B2 antibody which is and human CEA or transferrin (TF) was conjugated to prepared the pendant type immunoliposome (Fab'-PEG-ILP or TF-PEG-ILP, respectively). Both immunoliposomes showed the low RES uptake and the long circulation time, and resulted in enhanced accumulation of the liposomes in the solid tumor. TF-PEG-ILP could internalize into tumor cells with receptor mediated endocytosis following extravasation into tumor tissue. The pendant type immunoliposome can escape from the gaps between adjacent endothelial cells and openings at the vessel termini during tumor angiogenesis by passive convective transport much rather than ligand directed targeting. Targeting to tumor tissue with the pendant type immunoliposome is particularly important for many highly toxic anticancer drugs for cancer chemotherapy. An ultimate goal of pendant type immunoliposome is the incorporation of a fusogenic molecule that would induce fusion of liposome following their binding to the target cells or their internalization by endocytosis. Such liposomal formulations should be useful for endocytotic internalization of plasmid DNA and other bioactive materials.

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Despite the development of numerous anticancer agents, solid tumors in general respond poorly to chemotherapy. An objective of DDS in cancer chemotherapy is to find methods by which anticancer agents selectively target solid tumors. Two main concepts constitute selective tumor targeting, active targeting and passive targeting. The former involves monoclonal antibodies or ligands to tumor related receptors which can target the tumor by utilizing specific binding ability between the antibody and antigen or between the ligand and its receptor. The latter system can be achieved by the so-called “EPR effect, the enhanced permeability and retention effect”. The EPR effect in solid tumor tissue was named according to the pathophysiological characteristics : (a) hypervasculature ; (b) incomplete vascular architecture ; (c) several vascular permeability factors stimulating extravasation within the cancer ; (d) little drainage of macromolecules and particulates. Macromolecules have long plasma half-lives because they are too large to pass through the normal vessel walls unless they are trapped by the reticuloendothelial system in various organs. Such macromolecular agents can diffuse out of tumor blood vessels, reach the solid tumor tissue effectively and be retained for a long period due to the EPR effect. A DDS development technique enabled intravenous administration of water-insoluble drugs without using organic solvents which are usually vital to dissolve such hydrophobic drugs but have toxic effects. I review here recent clinical studies for DDS and introduce our recent work on the micelle system.

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In order to enhance its lipophilicity and develop its efficacy, we synthesized lecithinized ascorbic acid (PC-AS), in which a lecithin was covalently bound to ascorbic acid (ASA), and its pharmacological activity was evaluated. Judging from IC₅₀ value to scavenge superoxide anion generated from hypoxanthine in combination with xanthine oxidase, the antioxidative activity of PC-AS was estimated about 60% of that shown by ASA. Also, PC-AS suppressed in vitro cell growth of Meth A-T. Although its potency was a little lower than that of ASA, dramatical suppression was observed under serum-free culture conditions. In addition, N-acetylcysteine (NAC), an and-oxidant, showed an additive inhibitory effect on cell growth in combination with PC-AS and ASA. Biodistribution study revealed that PC-AS persisted longer in the blood (AUC_0-240min ; 182.8 nmole min ml^-1) as compared to ASA (AUC_0-240min ; 79.35 nmole min ml^-1). It should be noted that intravenous pre-administration of PC-AS significantly and dose-dependently reduced the number of colony formation in an experimental murine pulmonary metastasis model. ASA had little effect. [³H]-labeled Meth A-T cells predominantly accumulated in the lung, metastatic target organ, which was reduced by PC-AS. Our in vivo study showed that PC-AS could not totally prevent pulmonary invasion of Meth A-T cells, however, PC-AS effectively inhibited the number of metastatic colony formation. PC-AS's potency was superior to that of unmodified ASA. These findings might be ascribed to lecithinization-induced biodistribution, antioxidative activity and cytotoxicity.

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2'-C-cyano-2'-deoxy-1-β-D-arabino-pentofuranosylcytosine (CNDAC), a novel antitumor nucleoside antimetabolite, has a new mechanism of action for damaging tumor cells. This compound showed potent growth inhibitory activity against various kinds of human tumor cells both in vitro and in vivo. Furthermore, 5'-phosphatidylation of the compound enhanced the antitumor activity. In the present study, we liposomalized 5'-O-dipalmitoylphosphatidyl derivative of CNDAC (DPP-CNDAC) and investigated the effect of DPP-CNDAC incorporation on the in vivo behavior of these liposomes by a non-invasive method using positron emission tomography (PET). Interestingly, liposomes composed of DPP-CNDAC and cholesterol (DPP-CNDAC/CH liposomes) were observed to have a tendency to accumulate in lungs. Furthermore, this accumulation was markedly enhanced in the mice bearing lung metastatic cancer. Therefore, we attempted to use these CNDAC/CH liposomes for lung targeting and to examine the therapeutic efficacy against lung metastatic cancer. In experimental model using highly lung metastatic murine B16BL6 melanoma cells, these liposomes significantly reduced the number of lung tumor colonies as well as the size of them in a dose dependent manner. On the contrary, reduced lung colonization was not seen by use of the formulation of conventional liposomes or soluble CNDAC. These results were coincident with the data of PET analysis, and suggesting the usefulness of DPP-CNDAC/CH liposomes for curing lung metastasis.

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There is no quantitative analysis on the relationship between antitumor effect and optimum conditions of liposomes as drug carriers. We have developed a physiological model which incorporates a cell kill kinetic model for the antitumor effects of free and liposomal DOX in mice. Antitumor effect predicted by this model showed an optimum rate of drug release from liposomes (∼10hr in half life) and this prediction was varified by animal experiments in vivo. There was a good relationship of antitumor effects between simulations and experiments, which validates our model. This model will provide useful information for optimization of drug carriers for anticancer drugs.

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We examined the effect of liposomalization on the changes of lipid peroxide level and glutathione peroxidase (GSHpx) activity in mice tissues after 3'-deamino-3'-morpholino-13-deoxo-10-hydroxycarminomycin (MX2) administration. The agreement of the decrease in body weight on the 4th day after double MX2 administration (3.0mg/kg/day×2days, i.p.) was similar to those after adriamycin (ADR) administration (15mg/kg, i.p.). The lipid peroxide level in the heart and liver significantly increased after MX2 double treatment. GSHpx activity in the heart decreased to 80% on the 2nd day after MX2 injection, compared to normal activity. However, these changes are smaller than those after ADR administration (15mg/kg). NADPH-dependent microsomal lipid peroxidation in mouse liver increased, induced more by MX2 than by ADR. The combination of α-tocopherol with MX2 suppressed the increase in the lipid peroxide level by MX2 whereas did not suppress the decrease in GSHpx activity. Thus, it is considered that two mechanisms are involved, i.e., the increase in the lipid peroxide level occurs due to the production of active oxygen from MX2 and due to MX2-induced inhibition of GSHpx. The liposomalization of MX2 suppressed both MX2 induced changes in lipid peroxide level and GSHpx activity. Namely, it is considered that MX2 induced toxicity by these changes were reduced by α-tocopherol combination or liposomalization of MX2.

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A new method for preparing large amounts of intestinal luminal pressure-controlled colon delivery capsule (PCDC) which employs a pharmaceutical coating machine, Hicoater-mini^®, has been developed. As a model drug, fluorescein (FL) powder was suspended with suppository base, polyethylene glycol (PEG) 1000, at 50°C, and was hardened in the capsular shape. The capsular shaped suppositories were coated with 5w/v % ethanolic EC (7G grade) solution by a coating machine. By increasing the coating time from 55min to 75min, the mean coating thickness of PCDCs increased. Several kinds of #0 PCDCs having the mean EC coating membrane thickness of 141±7 μm (type 1), 166±4 μm (type 2), 188±4 μm (type 3), 211±4 μm (type 4) as well as #2 PCDCs having thickness of 102±3 μm (type 5) and 110±5 μm (type 6) were administrated to beagle dogs. The mean first appearance times (Tis) of FL into the systemic circulation from #0 PCDCs were 2.3±0.5 for type 1, 3.3±0.5 for type 2, 4.8±1.0 for type 3 and 7.8±1.7hr for type 4 preparations while the mean Tis of #2 PCDCs were 3.2±0.4 for type 5 and 3.8±0.4 hr for type 6, respectively. Therefore, it was suggested that types 2, 3 and 5 PCDCs were delivered to the colon.

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Recently, following with the development of biotechnology, active core peptides of many bioactive proteins were identified and these bioactive peptides have been shown to be potential candidates for therapeutic agents. But their clinical application have been limited because of their low in vivo stability caused by enzymatic degradation and rapid renal excretion from blood. To enhance the therapeutic usefulness of bioactive peptide, a polymeric modifier, SMA (poly(styrene co-maleic anhydride)) which is known as binding to plasma albumin, was applied to conjugate a synthetic cell-adhesive laminin-derived peptide YIGSR, and their inhibitory effect on lung metastasis of B16BL6 melanoma cells were examined. SMA conjugated YIGSR (SMA-YIGSR) showed a marked antimetastatic effect than native peptide YIGSR in terms of molar ratio of YIGSR. In addition, SMA-YIGSR was found to bind efficiently to albumin by affinity chromatography but not YIGSR. So it is assumed that the binding to plasma albumin might result in a longer plasma half-life. In order to make the mechanism of enhancement of antimetastatic effect more clearly, now pharmacokinetics of SMA-YIGSR and binding affinity of SMA-YIGSR to albumin were on study.

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