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1.
Bioorg Med Chem ; 20(18): 5559-67, 2012 Sep 15.
Article in English | MEDLINE | ID: mdl-22892212

ABSTRACT

Four kinds of symmetrically branched oligoglyceryl trimeric (BGL003)-paclitaxel conjugates and a corresponding heptameric (BGL007) conjugate were synthesized. Molecular weights of all the compounds were less than two times that of paclitaxel. The anti-tumor activity of the most water-soluble BGL003 conjugate was examined and found to be preserved in spite of the chemical modification that is displacement of the N3'-debenzoyl residue with the BGL003 succinyl residue.


Subject(s)
Antineoplastic Agents, Phytogenic/chemical synthesis , Antineoplastic Agents, Phytogenic/pharmacology , Glycerol/chemistry , Glycerol/pharmacology , Neoplasms, Experimental/drug therapy , Paclitaxel/chemistry , Paclitaxel/pharmacology , Animals , Antineoplastic Agents, Phytogenic/chemistry , Cell Line, Tumor , Dose-Response Relationship, Drug , Humans , Male , Mice , Mice, Inbred BALB C , Mice, Nude , Molecular Conformation , Molecular Weight , Solubility , Structure-Activity Relationship , Xenograft Model Antitumor Assays
2.
Bioorg Med Chem Lett ; 22(15): 5051-4, 2012 Aug 01.
Article in English | MEDLINE | ID: mdl-22765896

ABSTRACT

Synthesis of four water-soluble resveratrol and piceatannol derivatives bearing symmetrically branched glyceryl trimer (BGL003) with a non-biocleavable linkage, and their biological evaluation as a mitochondrial fusion-inducing agent with cellular fat-reducing effect from cells, is described. The effect of Piceatannol-BGL003 conjugate was as high as that of original stilbenoids.


Subject(s)
Glycerol/chemistry , Stilbenes/chemistry , Glycerol/chemical synthesis , Mitochondria/metabolism , Resveratrol , Solubility , Stilbenes/chemical synthesis , Water/chemistry
3.
J Biomater Sci Polym Ed ; 23(16): 2055-68, 2012.
Article in English | MEDLINE | ID: mdl-22054261

ABSTRACT

Liposomes are recognized as potentially useful drug carriers but many problems preclude practical medical application. Liposomes bind with serum proteins (opsonization) and are captured by the reticuloendothelial system cells in the liver and spleen, which limits their ability to deliver drugs to other target sites. Modification of lipids with flexible, hydrophilic polymers such as poly(ethylene glycol) (PEG) to yield sterically stabilized liposomes is one approach to improve liposome blood circulation and tissue distribution properties. In this study, we examined liposomes prepared using lipids modified with a new branched oligoglycerol (BGL) moiety for steric stabilization. This novel BGL comprised 14 glycerol units (termed BGL014) connected with flexible ether linkages, resulting in a branched cascade-like structure that is highly expanded in aqueous solution. BGL014 was coupled to 1,2-distearoylphosphatidylethanolamine to yield BGL014-modified lipids. Incorporation of BGL014 into liposomes (BGL014L) resulted in long blood circulation times, despite a much thinner fixed aqueous layer thickness compared to PEG formulations. BGL014 produced a liposome surface coating that appears to function through steric inhibition of non-specific protein binding without strong interference of specific protein-binding reactions. Liposome structure and functionality was maintained following BGL014-modification, as the incorporation ratio of drug remained high. These results suggest that the BGL014 modification of liposomes is a promising approach to produce stable and long circulating drug carriers capable of selective binding to specific proteins.


Subject(s)
Glycerol/analogs & derivatives , Liposomes/chemistry , Polymers/chemistry , Administration, Intravenous , Animals , Antibiotics, Antineoplastic/administration & dosage , Blood/metabolism , Cattle , Doxorubicin/administration & dosage , Drug Carriers/chemistry , Glycerol/chemistry , Materials Testing , Molecular Structure , Polyethylene Glycols/chemistry , Rats, Sprague-Dawley , Serum Albumin, Bovine/chemistry , Solutions , Streptavidin/chemistry , Surface Properties , Water/chemistry
4.
Bioorg Med Chem Lett ; 21(16): 4724-7, 2011 Aug 15.
Article in English | MEDLINE | ID: mdl-21757340

ABSTRACT

Synthesis of a symmetrically branched diglycerol (BGL002, involving one iminodiacetic residue) as a G2 dendron, and the tetradecaglycerol (BGL014, involving one iminodiacetic residue) as a G4 dendron, is described. Several members of the BGL family of G2-G4 dendrons were assembled, with G2 bearing four hydroxyl groups at the terminus region, G3 bearing eight, and G4 bearing sixteen. It is noteworthy that triglycerol (BGL003, including no iminodiacetic residue), has a water-solubility ten times higher than BGL002, and the liposome surrounded by BGL014 has a duration period in blood vessel roughly two times longer than the liposome surrounded by dodecaglycerol (BGL012, including three iminodiacetic residues).


Subject(s)
Glycerol/chemical synthesis , Imino Acids/chemistry , Glycerol/analogs & derivatives , Glycerol/chemistry , Molecular Structure , Stereoisomerism
5.
Int J Pharm ; 391(1-2): 237-43, 2010 May 31.
Article in English | MEDLINE | ID: mdl-20298767

ABSTRACT

We examined the effect on drug delivery of liposomes with surfaces that were modified with branched oligoglycerols (BGLs) and explored possible formulation advantages to increase drug exposure. BGL012 is a branched oligoglycerol derivative with a cascade-like structure of 12 glycerol units, characterized as a widely spread structure in aqueous solution. We prepared BGL-phospholipid derivatives (BGL-PEs), including BGL012, by coupling 1,2-distearoylphosphatidylethanolamine to BGLs. BGL012-PE modification of the liposomes (BGL012L) achieved a long circulation time after intravenous injection in rats. The circulation lifetime of BGL012L was almost the same as that of polyethylene glycol (PEG)-modified liposomes. The surface of BGL012L induced the formation of a fixed aqueous layer and reduced protein adsorption on the liposome surface, without strong interference with the binding reaction on the liposome. Thus, the newly synthesized branched oligoglycerol derivatives are considered to have useful hydrophilic and physical properties for modifying the liposome surface to increase drug exposure.


Subject(s)
Blood Proteins/pharmacokinetics , Drug Compounding/methods , Glycerol/analogs & derivatives , Liposomes/administration & dosage , Adsorption/drug effects , Animals , Chemistry, Pharmaceutical/methods , Doxorubicin/pharmacokinetics , Drug Stability , Glycerol/chemistry , Injections, Intravenous , Liposomes/blood , Liposomes/chemical synthesis , Liposomes/chemistry , Male , Phosphatidylethanolamines/chemistry , Phospholipids/chemical synthesis , Rats , Rats, Inbred Strains , Streptavidin/chemistry , Surface Properties
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