Drug carriers are useful tools for controlling the in vivo disposition of drugs. The distribution of carriers are determined by their tissue interaction depending on the anatomical and physiological characteristics of each tissue and the physicochemical and biological properties of carriers. Once these properties of carriers are quantitatively correlated with their tissue distribution, a proper drug carrier can be rationally developed. However, this is not the case for carriers which interact with blood components, such as blood cells and plasma proteins, before reaching to their targets. The properties of carriers will be altered by such interactions, which leads to various changes of the biofates of carriers. Carriers interact with plasma proteins in different ways : nonspecific interaction (adsorption), recognition by immune proteins, and metabolism and exchange of lipids. In general, the more plasma proteins bind to carriers, the faster they are eliminated from the blood circulation. Positively-charged carriers like cationic liposomes interact with negatively-charged plasma proteins, which sometimes leads to the aggregation of carriers and the embolization of blood vessels after intravascular administration. When drug carriers are recognized as non-self, they are removed by the mononuclear phagocyte system(MPS). The binding of immunoglobulins and complements to carriers extremely facilitates their removal by MPS. Mannan binding protein, an immune protein which recognize mannose or N-acetylglucosamine residue on virus infected cells, can interact with carriers possessing mannose moieties. In addition, binding of apolipoproteins triggers the metabolism of o/w emulsions followed by their uptake by hepatocytes via apolipoprotein E-specific receptors. To regulate in vivo distribution of drug carriers, therefore, their interactions with plasma proteins should be suppressed. Coating of carriers with hydrophilic macromolecules, such as poly(ethylene glycol) and ganglioside G_M1, is a promising approach to suppress such interactions. In conclusion, we can theoretically develop a well-designed drug carrier system by considering its interactions with blood components as well as with tissues.

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The concept of drug delivery system (DDS) was born approximately 30 years ago and developed in many aspects such as controlled release, absorption enhancement and targeting. New aspect in DDS is required for gene therapy with highly controlled delivery system especially to control the intracellular trafficking of carrier as well as DNA. Multi-functional carrier system will he required to overcome the barriers such as plasma membrane, endosomal membrane and nuclear membrane. Receptor-mediated endocytosis is one of the most selective and efficient entrance pathway for gene delivery, however, endosomal escape is then a critical barrier for efficient cytosolic delivery. pH-sensitive liposome is able to deliver encapsulated macromolecules into cytosol depending on the decreased endosomal pH. Active targeting to nuclear compartment is essential, otherwise DNA will be degraded in cytosol. Nuclear localization signals have been identified and used for nuclear delivery of macromolecules including DNA. For the rational optimization of the carrier system for gene delivery, quantitative assay of DNA in each organella should be critical. New method in measuring the amount of DNA in nucleus has been established using PCR amplification method. This method can be applied to measure intracellular amount of DNA in other organella, which leads to optimize the intracellular trafficking of DNA with artificial carrier and to surpass the efficiency of virus.

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In the present study, we investigated the resistance of plasmid DNA, which is formed a complex with cationic liposomes, to nuclease using pGreen Lantern plasmid coding green fluorescent protein of Aquorea victoria jellyfish. Native plasmid DNA was digested easily with above 10% of fetal bovine serum and 1 × 10^-4 units of DNase I from bovine pancreas by the estimation of agarose-gel electrophoresis. On the other hand, plasmid DNA complexed with cationic liposomes composed of TMAG exhibited the resistance to DNase, and relaxed and supercoiled plasmid DNA were observed on the same electrophoretic mobility at the same intensity as control plasmid. The degradation of plasmid DNA by DNase was estimated quantitatively with NIH image plot profile analysis, and the recovery of plasmid DNA showed the almost same values irrespective of DNase treatment. These findings suggest that plasmid DNA acquires the resistance to DNase on account of the complex formation with cationic liposomes.

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This study was undertaken to evaluate feasibility of metal coordination as a method to prepare a protein drug-polymer conjugate. A metal chelating, diethylenetriaminepentaacetic acid (DTPA) residue was introduced to a polysaccharide, dextarn for metal coordination. Recombinant human tumor necrosis factor α(TNF) was used as a protein drug. A simple mixing with the DTPA-dextran in an aqueous solution containing Cu²⁺ enabled TNF to coordinately conjugate to dextran. Following intravenous (i.v.) injection into tumor-bearing mice, the TNF-DTPA-Dextran conjugate exhibited a significantly higher tumor accumulation of TNF and the longer retention period than free TNF or its mixture with the DTPA-dextran. I. V. injection of the TNF-DTPA-dextran conjugate suppressed tumor growth to a significantly greater extent than that of free TNF even at a lower injection dose. We concluded that dextran conjugation based on Cu²⁺ coordination was a promising way to enhance the antitumor effect of TNF as a result of its passive tumor targeting.

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We previously reported that 1-methyl-3-propy1-7-butylxantlaine (MPBX), a novel xanthine derivative, enhanced the antitumor activity of doxorubicin (DOX) due to inhibition of the DOX efflux from tumor cells. In this study, we investigated the effects of MPBX not only on drug sensitive tumor but also on multidrug resistant or metastatic tumors with the aim of developing its clinical use. In Ehrlich carcinoma bearing mice, MPBX enhanced antitumor activity of DOX 1.8-fold and increased the DOX concentration in the tumor 1.6-fold. Moreover, on multidrug resistant P388 leukemia (P388/DOX), DOX + MPBX significantly reduced the tumor weight to 48% of control level, whereas DOX alone did not reduce the tumor weight. MPBX increased the DOX influx into P388/DOX cells and inhibited the DOX efflux in vitro, supporting the increase in the DOX concentration in the tumor induced by MPBX in vivo. Furthermore, MPBX enhanced the therapeutic efficacy of pirarubicin, an anthracycline antibiotic, against metastatic M5076 sarcoma. In conclusion, MPBX enhanced the antitumor activity of anthracycline agents on sensitive, multidrug resistant or metastatic tumors. Thus, we expected that MPBX would be used as a biochemical modulator in clinical cancer chemothrapy.

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Hydroxyapatite(HAp) particles has excellent compatibility with human tissue and can be safely administered into the peritoneal cavity of rats with no significant complications (Artif. Organs Today 3 : 185-192, 1994). We explored the possibility of HAp as a drug carrier for carboplatin using AH130 abdominal carcinomatosis. HAp particles are biodegradable following intraperitoneal administration(i. p.) and were taken up especially in greater omentum. The pharmacokinetics of HAp-CBDCA were examined using Donryu rat models with AH130 abdominal carcinomatosis. The platinum(Pt) levels in serum and ascites were higher in HAp-CBDCA i. p. than free-CBDCA i. v. groups. HAp-CBDCA i. p. were effective in prolonging the survival of rats model with AH130 abdominal carcinomatosis. HAp-CBDCA administration was experimentally confirmed to be safe. For the clinical application, HAp-CBDCA (HAp-particles : 5 g, CBDCA : 150 mg) was administered into the pleural cavity(i. pc.) at operation on the two advanced esophageal cancer and the pharmacokinetics of CBDCA were also examined. The serum levels of Pt were higher in the HAp-CBDCA(i. pc.) from 5 minute to 30 minute than those in the free-CBDCA(i. pc.). These results demonstrated the efficacy of HAp particles as a drug carrier for anticancer drugs, with ultimate improvement in overall survival.

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To determine the necessary technology by which sustained drug release is obtained after drug is delivered to the colon, two kinds of microcapsules were prepared and were filled in a pressure-controlled colon delivery capsule (PCDC). 5-aminosalicylic acid (5-ASA) was microencapsulated with a water-insoluble polymer, ethylcellulose (EC) or with pH-sensitive polymers, Eudragit^™ L-100 or S-100 and encased in PCDC, After oral administration of the test preparations to beagle dogs, the first appearance time of 5-ASA into the systemic circulation were 3 hr for all the colon delivery preparations. These test preparations were thought to be delivered to the colon. Both EC microcapsules and Eudragit S/RS microcapsules in PCDC showed longer mean residence time MRT, 8.2±0.6 hr and 8.7±0.9 hr, than Eudragit L/RS microcapsules in PCDC of which MRT was 6.6±0.2 hr, Since PCDC containing 5-ASA powder exhibited a MRT of 7.0±1.0 hr, these two types of preparations have sustained release characteristics.

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