Preparation and properties of branched oligoglycerol modifiers for stabilization of liposomes

Ishihara, Atsushi; Yamauchi, Masahiro; Kusano, Hiroko; Mimura, Yukiteru; Nakakura, Masashi; Kamiya, M.; Katagiri, Ayato; Kawano, Masaki; Nemoto, Hisao; Suzawa, Toshiyuki; Yamasaki, Motoo

doi:10.1016/j.ijpharm.2010.03.031

Cited by 15 publications

(7 citation statements)

References 30 publications

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“…We have previously shown that BGLation strikingly improved physical properties including hydrophilicity of lipophilic molecules (Ishihara et al, 2010Nemoto et al, 2007aNemoto et al, , 2011Nemoto et al, , 2012aNemoto et al, , 2012bYamaguchi et al, 2008). Recently we succeeded in synthesizing a novel molecule, BGL003-conjugated fenofibrate (FF-BGL) (Fig.…”

Section: Resultsmentioning

confidence: 92%

“…Therefore, we have designed symmetrically branched oligoglycerols (BGL) such as the trimer (BGL003) (Fig. 1A), of which molecular weight is as small as 240.25, as alternative highly hydrophilic modular molecules and have shown that stability in circulation and water-solubility of such molecules as proteins, liposomes and hydrophobic compounds were much improved by conjugation to BGL (BGLation) (Ishihara et al, 2010Nemoto et al, 1999Nemoto et al, , 2007aNemoto et al, , 2007bNemoto et al, , 2010Nemoto et al, , 2011Nemoto et al, , 2012aNemoto et al, and 2012bYamaguchi et al, 2008). Albeit these beneficial effects of BGLation, little was known whether BGL could be used in safety.…”

Section: Introductionmentioning

confidence: 99%

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Cytotoxicity evaluation of symmetrically branched glycerol trimer in human hepatocellular carcinoma HepG2 cells

et al. 2012

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-An appropriate balance between lipophilicity and hydrophilicity is necessary for pharmaceuticals to achieve fine Absorption, Distribution, Metabolism and Excretion (ADME) properties including absorption and distribution, in particular. We have designed and proposed symmetrically branched oligoglycerols (BGL) as an alternative approach to improve the lipophilic-hydrophilic balance. We have previously shown that stability in circulation and water-solubility of such molecules as proteins, liposomes and hydrophobic compounds are much improved by conjugation to BGL. Albeit these successful applications of BGL, little was known whether BGL could be used in safety. Thus we conducted evaluation of the cytotoxicity of a representative BGL, symmetrically branched glycerol trimer (BGL003) in the cultured cells to clarify its biological safeness. Here we demonstrate that water-solubility of an extremely hydrophobic agent, fenofibrate was more than 2,000-fold improved just by conjugated with BGL003. BGL003 did not exhibit any significant cytotoxicity in human hepatocarcinoma HepG2 cells. Thus BGL003 should be safe and suitable strategy to endow hydrophobic molecules with much hydrophilicity.

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Section: Resultsmentioning

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Cytotoxicity evaluation of symmetrically branched glycerol trimer in human hepatocellular carcinoma HepG2 cells

et al. 2012

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“…A classical way of stabilizing vesicles consists in incorporating PEG-ylated lipids into the membrane which leads to steric stabilisation. [14][15][16][17][18][19] Similarly the adsorption of polyelectrolyte (chitosan and hyaluronan) has been found to stabilize vesicles against pH, osmotic and salt shocks. [20][21][22] More recently, novel strategies involving charged nanoparticles have been proposed in order to achieve the stabilisation of liposomes.…”

Section: Introductionmentioning

confidence: 99%

Control of the stability and structure of liposomes by means of nanoparticles

et al. 2013

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The interaction of bilayer vesicles with hard nanoparticles is of great relevance to the field of nanotechnology, e.g., its impact on health and safety matters, and also as vesicles are important as delivery vehicles. In this work we describe hybrid systems composed of zwitterionic phospholipid vesicles (DPPC), which are below the phase transition temperature, and added silica nanoparticles (SiNPs) of much smaller size. The initial DPPC unilamellar vesicles, obtained by extrusion, are rather unstable and age but the rate of ageing can be controlled over a large time range by the amount of added SiNPs. For low addition they become destabilized whereas larger amounts of SiNPs enhance the stability largely as confirmed by dynamic light scattering (DLS). z-Potential and DSC measurements confirm the binding of the SiNPs onto the phospholipid vesicles, which stabilizes the vesicles against flocculation by rendering the z-potential more negative. This effect appears above a specific SiNP concentration, and is the result of the adsorption of the negatively charged nanoparticles onto the outer surface of the liposome leading to decorated vesicles as proven by cryogenic transmission electron microscopy (cryo-TEM). Small amounts of surface-adsorbed SiNPs initially lead to a bridging of vesicles thereby enhancing flocculation, while higher amounts render the vesicles much more negatively charged and thereby longtime stable. This stability has an optimum at neutral pH and for low ionic strength. Thus we show that the addition of the SiNPs is a versatile way to control the stability of gel-state phospholipid vesicles and also to modulate their surface structure in a systematic fashion. This is not only of importance for understanding the fundamental interaction between SiNPs and bilayer vesicles, but also with respect to using silica particles as formulation aids for phospholipid dispersions.

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“…1B). We have successfully improved stability in circulation and water-solubility of such molecules as proteins, liposomes and hydrophobic compounds by conjugation to BGL to date (Ishihara et al, 2010(Ishihara et al, , 2012Nemoto et al, 1999Nemoto et al, , 2007aNemoto et al, , 2007bNemoto et al, , 2010Nemoto et al, , 2011Nemoto et al, , 2012aNemoto et al, and 2012bYamaguchi et al, 2008). In the accompanying paper, we demonstrated that hydrophilicity and water-solubility of fenofibrate, a quite hydrophobic anti-hyperlipidemic drug (Fig.…”

Section: Introductionmentioning

confidence: 99%

Acute oral toxicity evaluation of symmetrically branched glycerol trimer in ddY mice

et al. 2012

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-Lipophilic-hydrophilic balance is a quite important determinant of pharmacokinetic properties of pharmaceuticals. Thus it is a key step to successfully manage lipophilic-hydrophilic balance in drug design. We have designed unique modular molecules, symmetrically branched oligoglycerols (BGL) as an alternative means to endow hydrophobic molecules with much hydrophilicity. We have succeeded in improving the water-solubility of several hydrophobic medicinal small molecules and thermal stability of artificial protein by covalent conjugation to BGL. We have also demonstrated that a representative BGL, symmetrically branched glycerol trimer (BGL003) does not exhibit significant cytotoxicity against human hepatocarcinoma HepG2 cells. However, there have been no reports suggesting whether BGL could be used in safety in vivo. Therefore, evaluation of acute oral toxicity of BGL003 in healthy mice was conducted. Here we demonstrate that an oral administration of BGL003 did not exhibit acute lethal toxicity up to 3,000 mg/kg. Body weight, food intake, blood glucose levels and weights of tissues were not affected by a short-term repetitive administration of increasing doses of BGL003. Biochemical indications related to hepatic disorders and tissue damage were unchanged, either. A single administration study revealed that 50% lethal dose of BGL003 should be more than 2,000 mg/kg. BGL003 will be safe and suitable approach to improve hydrophilicity of hydrophobic compounds.

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Preparation and properties of branched oligoglycerol modifiers for stabilization of liposomes

Cited by 15 publications

References 30 publications

Cytotoxicity evaluation of symmetrically branched glycerol trimer in human hepatocellular carcinoma HepG2 cells

Cytotoxicity evaluation of symmetrically branched glycerol trimer in human hepatocellular carcinoma HepG2 cells

Control of the stability and structure of liposomes by means of nanoparticles

Acute oral toxicity evaluation of symmetrically branched glycerol trimer in ddY mice

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