Hiroyuki Kojima

Evaluation of circulation profiles of liposomes coated with hydrophilic polymers having different molecular weights in rats

The purpose of this study was to evaluate the circulating properties of liposomes coated with modified polyvinyl alcohol (PVA-R) having different molecular weights (6000, 9000 and 20000). The size controlled liposomes (egg phosphatidylcholine (or distearoylphosphatidylcholine):cholesterol=7:3 in a molar ratio) were prepared by the hydration method followed by sonication. Polymer coated liposomes were prepared by just mixing the resultant liposomal suspension and a polymer solution. The effects of polymer coating were evaluated by measuring the circulation time of the injected liposomes after i.v. administration in rats and the dispersing property of the liposomes in a biological condition. The circulation of the PVA-R coated liposomes was prolonged with increasing the molecular weight of PVA-R. The aggregation and/or fusion of the liposomes in the presence of serum in vitro was also depressed more by coating the liposomes with PVA-R having higher molecular weight. There was a good correlation between the circulation time and the physical stability of non-coated and the various PVA-R coated liposomes. The prolonged circulation time of PVA-R (molecular weight: 20000) coated liposomes (ca. 1.3 mol% coating) was comparable to that of a stealth liposome prepared with 8 mol% of DSPE-PEG (molecular weight of PEG: 2000).

Polymer coating of liposomes with a modified polyvinyl alcohol and their systemic circulation and RES uptake in rats.

The objective of this study was to evaluate the in vivo characteristics of liposomes coated with a polyvinyl alcohol having a long alkyl chain at the end of the molecule (PVA-R) as an injectable drug carrier for passive targeting of drugs. A fluorescence marker, cholesteryl-anthracene-9-carboxylate, was incorporated into the liposomes to detect their concentration in the plasma and organs. The small unilamellar liposomes (100 nm in diameter) with various lipid compositions, such as the different cholesterol contents or the different charges, were prepared by the hydration method followed by sonication and coated with PVA or PVA-R by just mixing the resultant liposomal suspensions with the polymer solutions. The circulation and distribution of the liposomes were tested with their intravenous administration in rats. The PVA-R-coated liposomes showed significantly higher circulation compared to that of non-coated ones in any liposomal formulation tested. The prolonged circulation of PVA-R-coated liposomes was attributed to their fewer uptake in liver and spleen. The extent in improvement in the in vivo characteristics were well interpreted by the hydrophobicity of liposomes and their coating amount of PVA-R. It was also demonstrated that the liposomes having a positive and a negative charge, which showed the completely different circulating profiles, showed almost the same profile by coating with PVA-R. When the liposomes were coated with PVA the improvement in blood circulation was much less in any cases, although coating layer of PVA was detected. These results confirm that not only the hydrophilic property but the sterically stabilizing effect of the coating layer is important to prolong the circulation of the particulate drug carriers with less RES uptake, and the PVA-R having a hydrophobic moiety at the end of the molecule of PVA is a suitable material for the coating of liposomes.

Prolonged circulation time of doxorubicin-loaded liposomes coated with a modified polyvinyl alcohol after intravenous injection in rats

The purpose of this study was to evaluate the functions of a modified polyvinyl alcohol (PVA-R), which has a hydrophobic moiety, as a coating material for liposomes to be loaded with the anticancer drug, doxorubicin. The size controlled liposomes (egg phosphatidylcholine: cholesterol=1:1 molar ratio) were prepared by the hydration method followed by extrusion. Drug encapsulation and surface modification with polymers (PVA and PVA-R) were carried out simultaneously using a modified pH gradient method. The existence of a thick polymer layer on the surface of the liposomes was confirmed by an increase in particle size and the amount of polymer on the liposomal surface, especially for the PVA-R-coated liposomes. The effects of polymer coating on the behavior of the liposomes in vivo were evaluated by measuring the circulation time and biodistribution of the drug after i.v. administration of the liposomal drug in rats. The PVA-R-coated liposomes showed a more prolonged circulating time for the drug with less uptake by the reticuloendothelial system after i.v. administration in rats, compared with non-coated liposomes. These results confirm that polymer possessing a hydrophobic anchor at its end, like PVA-R, is a suitable material for modifying the surface of doxorubicin-loaded liposomes to improve their stability in the circulating blood.

Phenolic constituents from seeds of Coptis japonica var. dissecta

Abstract In addition to coumarinolignans (cleomiscosin A aquillochin) and 7,4′-dihydroxy-5-methoxyflavanone, a new dihydrochalcone, 2′,4,4′-trihydroxy-6′-methoxydihydrochalcone, was isolated from the seeds of Coptis japonica var. dissecta. The structure of the dihydrochalcone was confirmed by comparison with relevant synthetic samples.

Coumarin derivatives in Coptis trifolia

Abstract Known compounds, epiberberine, groenlandicine, scopoletin and β-sitosterol were characterized in the whole plants of Coptis trifolia . By means of spectral analysis, the structures of two new compounds were determined to be glycosides of a 10-hydroxygeranyl residue which is linked with scopoletin (7-hydroxy-6-methoxycoumarin) through an ether linkage.

Enhanced Tumour Accumulation of Doxorubicin with Polymer-coated Liposomes in Rats

Doxorubicin-loaded liposomes composed of egg phosphatidylcholine and cholesterol (1:1 molar ratio) were coated with polyvinylalcohol and hydroxypropylmethylcellulose derivatives (PVA-R and HPMC-R, respectively) and evaluated after intravenous injection in rats bearing Walker rat carcinoma 256 cells. n n n nPolymer-coated liposomes exhibited significantly higher drug levels in the blood than uncoated liposomes. The concentration of doxorubicin in solid tumour was evaluated 24 h after injection of polymer-coated liposome and uncoated liposomes. Polymer-coated liposomes showed 2–03 (PVA-R) and 1.94-times (HPMC-R) higher concentrations in the tumour than uncoated liposomes. This difference was still evident 48 h after injection. n n n nThe results indicate that long-circulating polymer-coated liposomes could enhance the efficiency of anticancer agents by the selective accumulation of drugs at the tumour site.

Kaempferol glycosides in Asplenium scolopendrium newm.

Abstract Five kaempferol glycosides in the fronds of Asplenium scolopendrium were isolated . The structures of three novel flavonol glycosides were determined to be kaempferol 3-O -β-D -glucopyranosyl-( 1→3 )-β -D -(2 -O -caffeoyl)glucopyranoside 7 -O -α -L -rhamnopyranoside , kaempferol 3 -O -β -D -glucopyranosyl-(1→3 )-β -D -glucopyranoside 7 -O -α -L -rhamnopyranoside and kaempferol 3 -O -(2 -O -caffeoyl)-β -D -glucopyranoside 7 -O -α -L -rhamnopyranosideby means of spectral data (FAB-M S, 1H-1H, 1H -13C COSY and 1H-13C long range COSY), respectively.

Mearnsetin 3,7-dirhamnoside from Asplenium antiquum

Abstract A new flavonol glycoside from the fronds of Asplenium antiquum was isolated and the structure elucidated as mearnsetin 3,7-di- O -α- l -rhamnopyranoside by means of spectral anaysis.