With a rapid demand to decrease the side effect of drug, a variety of drug delivery systems have been developed. This review will focus on the development of liposomes with soybean-derived sterols and their glucosides for drug carriers. Current status and further perspectives in this research field are reviewed mainly based on the results obtained in our laboratory. First we studied the different physicochemical properties of dipalmitoylphosphatidylcholine (DPPC) liposomes with soybean-derived sterols (SS) and their glucosides (SG). SS rigidifies the liposomal membrane but SG fluidizes it. SS stabilizes liposomes more than cholesterol that is conventionally used as stabilizing agents in liposomes. On the basis of this information, we developed liposomes with SS and SG for a drug carrier. Secondly we studied the stability of liposomes in the blood and biodistribution and found that liposomes with SS were stable as expected in vitro results. In particular, DPPC : SS (7 : 4, molar ratio) size 0.2 μm showed long circulation. Thirdly successful targeting of the drugs to the liver was achieved by liposomes with SG. Finally, we succeeded in developing liposomal erythropoietin and doxorubicin using liposomes with SS for sustained release of drugs. Liposomal drugs increased the pharmacological effect compared with free drugs, suggesting a decrease of side effect and long circulation. The attempt for oral administration using liposomes of peptide drugs was carried out successfully. We have established that the study of physicochemical properties of liposomes is needed rationally as the distribution of drugs in liposomes and the rigidity of liposomal membrane, prior to the development of the drug carrier of liposomes. SS is useful to stabilize liposomes and SG to targeting to the liver parenchymal cells. This information can be useful and practical for the development of liposomes for drug carriers.
A series of scientific expeditions in Indonesia for collecting informations and materials concerning locally used medicinal plants and Javanese traditional medicine"jamu"have been carried out by us since 1985. This article reviews pharmacochemical investigations of nine Indonesian medicinal plants : i.e. Pongamia pinnata (Papilionaceae), Fagara rhetza (Rutaceae), Calotropis gigantea (Asclepiadaceae), Beilschmiedia madang (Lauraceae), Caesalpinia major (Fabaceae), Peronema canescens (Verbenaceae), Taxus sumatrana (Taxaceae), Alyxia reinwardtii (Apocynaceae), and Merremia mammosa (Convolvulaceae), which were selected among plant materials collected in those surveys.
Retinoids, retinoic acid and its bioisosters, regulate many biological functions such as cell differentiation, proliferation and embryonic development in vertabrates, through binding to and activating their specific nuclear receptors. There are two classes of nuclear receptors for retinoids, retinoic acid receptors (RARα, β, γ) and retinoid X receptors (RXRα, β, γ). Several retinoid antagonists, which bind to but not activate RARs, have been reported. Among them, 4-(5H-7, 8, 9, 10-tetrahydro-5, 7, 7, 10, 10-pentamethylbenzo [e] naphtho [2, 3-b] [1, 4] diazepin-13-yl) benzoic acid (LE135, 20) is a RARβ-selective retinoid antagonist. Structure-activity relationships of LE135 (20) showed that the naphthalenyl analogs [LE540 (21) and LE550 (22)] are more potent retinoid antagonists in HL-60 assay. Contrary to the antagonistic activity of LE135 (20), an isomer of LE135 (20), 4-[5H-2, 3-(2, 5-dimethyl-2, 5-hexano)-5-methyldibenzo-[b, e] [1, 4] diazepin-11-yl) benzoic acid (HX600, 39) enhanced the activities of retinoids. Although the synergistic activity of HX600 (39) can be explained by the binding to RXRs and the further activation of RAR/RXR heterodimer activated by retinoid (RAR ligand), the significantly different biological character of HX600 (39) from the typical RXR-selective ligand suggested the possibility of the participation of other nuclear receptors or cofactors in the retinoid synergism.
Remarkably high inhibitory effects of the hybrid liposomes composed of L-α-dimyristoyl-phosphatidylcholine (DMPC) and polyoxyethylenealkyl ether (C14 (EO)n, n=6-8 and C12 (EO)n, n=8-12)) on the growth of human lymphoma-human B-lymphocyte hybridoma (HF) cells in vitro were obtained. The hybrid liposomes composed of 90 mol% DMPC/10mol% C14 (EO)n (n=6-8) or C12 (EO)n (n=8-12) were more fluid as compared with 90mol% DMPC/10 mol% C14 (EO)4 or C12 (EO)n (n=4, 23) hybrid liposomes on the basis of fluorescence polarization measurements. These results suggest that the inhibitory effects of the hybrid liposomes on the growth of HF cells should be related to the membrane fluidity. No toxicity to normal rats in vivo was observed in the experiment using 90mol% DMPC/10mol% C14 (EO)7 or 90mol% DMPC/10mol% C12 (EO)12 hybrid liposomes.
We investigated whether a chemical assay by high-performance liquid chromatography (HPLC) as an alternative to the complicated and time-consuming bioassay for CS23 mutein of recombinant human basic fibroblast growth factor (rhbFGF-CS23) using the fetal bovine heart endothelial cell line ATCC CRL 1395. Physically, chemically or enzymatically denatured rhbFGF-CS23 was subjected to heparin affinity (HA)-HPLC and the bioassay. Good agreement was observed between the results obtained by these two methods. Moreover, HA-HPLC gave much more reproducible results (RSD=1.9%, n=6) than the bioassay (RSD=7.4%, n=18). HA-HPLC is therefore a simple, accurate and reproducible alternative to the bioassay for quality control and stability studies for rhbFGF-CS23 preparations. HA-HPLC is also considered to be applicable to assays for FGFs which have heparin affinity and biological activity similar to those of the CS23 mutein.