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

Abstract

-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.

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

“…These results demonstrated that acute toxicities on tissues including hepatotoxicity of BGL003 should be as low risk causing as glycerol, which is widely used in miscellaneous commodities around us including foods and medicines, if it exists. It is quite consistent with our result in the accompanying paper that BGL003 did not show significant cytotoxicity against human hepatocarcinoma HepG2 cells (Miyamoto et al, 2012). Our data above suggest adequate tolerability of BGL003 in vivo.…”

“…1E) (Nemoto et al, 2012c;Miyamoto et al, 2012). We recently noticed that the BGL003-conjugated fenofibrate yielded an active form of fenofibrate, fenofibric acid (Fig.…”

“…1C), was improved more than 2,000-times by conjugation to BGL003 (Fig. 1E) (Miyamoto et al, 2012). Albeit these benefits of BGL, little was known whether BGL could be used in safety especially in vivo.…”

Methanol extraction fraction from Citrus Sudachi peel exerts lipid reducing effects in cultured cells

“…Cell viability was evaluated by MTT ((3 -(4,5 -di-methylthiazol-2yl)-2,5-diphenyltetrazolium bromide) assay as previously described (12,19,21).…”

Expanding frontiers in weight-control research explored by young investigators

“…Membrane permeability is correlated with lipophilicity, usually estimated using the logarithm of the n -octanol/water partition coefficient (log Po/w) [32]. The log Po/w of γ-oryzanol has been calculated as 12.1 using the XLOGP3 method [33], while that of fenofibrate, one of the most lipophilic agents among the clinically-used drugs, is 5.19 [34, 35]. This suggests that γ-oryzanol should be lipophilic enough to be membrane permeable and thus may influence intracellular metabolism.…”