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

Abstract

-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.

Novel Hydrophilic Camptothecin Derivatives Conjugated to Branched Glycerol Trimer Suppress Tumor Growth without Causing Diarrhea in Murine Xenograft Models of Human Lung Cancer

“…Even if BGL003 is cut out in the body, we have confirmed its biological safety by evaluating acute oral toxicity in mice and cytotoxicity, although our digestion study suggests that BGL003 was not expected to be produced by hepatic drug conversion (Figures 7 and 8). 12,15 We also have demonstrated striking facilitation of lipid-lowering effects and hydrophilicity of fenofibrate by conjugating to BGL003. 14 The study revealed that the BGL003-conjugated fenofibrate derivative is a prodrug and rapidly cleft, producing BGL003free fenofibric acid when administered to rodents, while SN38-BGL A did not yield free SN38.…”

“…However, CPT-11 still has low water solubility, and other hydrophilic derivatives of camptothecin like PEG-conjugated SN38 have been explored to minimize adverse effects and maximize the pharmacological merits. − We have been developing another versatile strategy to endow hydrophobic molecules with much hydrophilicity by conjugating with branched glycerol oligomers. − The water solubility of fenofibrate, one of the most hydrophobic agents in clinical use, was >2000-fold improved just by conjugating to branched glycerol trimer (BGL003) . Furthermore, the BGL003-conjugated fenofibrate exhibited >10-fold stronger lipid-lowering effects as well as ∼5-fold higher concentrations in blood in rodent models. , In addition, the biological safety of BGL003 has been confirmed in terms of acute oral toxicity and cytotoxicity. , Therefore, the conjugation with branched glycerol oligomers could be a prospective way to ameliorate camptothecin-derived compounds.…”

“…13,14 In addition, the biological safety of BGL003 has been confirmed in terms of acute oral toxicity and cytotoxicity. 12,15 Therefore, the conjugation with branched glycerol oligomers could be a prospective way to ameliorate camptothecin-derived compounds.…”

Can food factors provide Us with the similar beneficial effects of physical exercise?

“…Many phytochemicals, especially, polyphenols are too hydrophobic to be absorbed into the body enoughly. We have been developing a novel technology for improving water-solubility of the hydrophobic molecules by conjugating it with branched glycerol oligomers (BGLs) (11,(54)(55)(56)(57). Pharmacological, pharmacokinetic, and physical properties of such highly hydrophobic compound as fenofibrate were strikingly ameliorated when conjugated with the BGL trimer without any adverse effects.…”

A Novel Prodrug Strategy for Extremely Hydrophobic Agents: Conjugation to Symmetrically Branched Glycerol Trimer Improves Pharmacological and Pharmacokinetic Properties of Fenofibrate

“…5−15 In addition, we have demonstrated biological safety of BGL003, the simplest BGL in cultured cells and rodents, suggesting BGL is innoxiously applicable to a prodrug. 15,16 However, it remained unclear whether the molecular modification by conjugation to BGL actually improves ADME properties of pharmaceuticals in terms of pharmacological effects.…”