| Rhamnolipids are versatile biosurfactants possessing excellent surface/interfacial activity and low toxicity and thus can be potentially applied in the pharmaceutical industries. As USEPA reported, rhamnolipids have good safety according to a high oral administration in rats with a high dose of 5000 mg/kg. However, rhamnolipids were indicated of the high cytotoxicity the in vitro cell culture. The contradiction between in vivo and in vitro has not been investigated. Therefore, this manuscript will study the cytotoxicity mechanism of rhamnolipids and explain the different sensitivies to rhamnolipids between in vivo and in vitro by in vitro models. And the novel potential application of rhamnolipids will be investigated as oral absorption enhancer and anti-fibrosis dr μ g.Firstly, the cytotoxicity of rhamnolipids was examined on two cancer cells (HepG2, Caco-2) and one normal cell (HK-2). Interestingly, both cancer and normal cells exhibited similar sensitivities to rhamnolipids, and the cytotoxicity was largely attenuated by fetal bovine serum (FBS) in culture medium. By correlating the mono-/di-rhamnolipids cytotoxicity with the surface tension of culture medium, it was found that cytotoxicity was triggered when the surface tension of culture medium decreased below about 41 mN/m, regardless the FBS content, cell line type, and rhamnolipids structure. Correspondingly, chemical surfactants (sodium dodecyl sulfate and sodium dodecyl benzene sulfonate) similarly caused cytotoxicity on HepG2 cells when the surface tension was under about 41 mN/m in culture medium. It seems that rhamnolipids, like chemical surfactants, exhibited cytotoxicity by reducing the surface tension of culture medium rather than by changing its specific molecular structure.Secondly, the higher safety of rhamnolipids in rats than in cell culture was explained by intravenous administration on rats and in vitro assays on absorption, distribution and metabolism. No significant toxicity except for a moderate liver enlargement and skin lesions was observed in intravenous administration of rats at the dose of 1500 mg/kg. The in vitro assays showed that the solubility of rhamnolipids in simulated gastric acid is about 900 mg/L, the plasma protein binding rate is about 92% and the hepatic extraction rate is about 65%. Thus, we assumed that the safety by oral administration could be explained by the low solubility of rhamnolipids in gastric acid, which limited the oral absorption of rhamnolipids. Further, both the strong protein binding ability and high hepatic elimination reduced their blood rhamnolipids concentrations, resulting in the less toxicity in vivo than in vitro.This work aimed to evaluate the applicability of rhamnolipids as permeation enhancers for oral drugs. In this study, rhamnolipids were found to effectively increase the paracellular and transcellular transport of Transwell-cultured Caco-2 cells at a concentration-dependent manner. Rhamnolipids at 150 mg/L increased almost 7.4 folds of the paracellular apparent permeability (Papp) and 2 folds of the transcellular pathway. Moreover, rhamnolipids significantly inhibited P-glycoprotein (P-gp) activity by 78%. In addition, rhamnolipids could enhance the permeability of anthocyanin 1.8-2.6 times by Transwell-cultured Caco-2 cell models.Finally, the anti-fibrosis effect of rhamnolipids was evaluated in the in vitro models whereas epithelium cell and fibrolast cell was induced into myofibroblasts at incubation with TGF-β1. It was found that rhamnolipids showed selective cytotoxicity on myofibroblast. Moreover, rhamnolipids inhibited the collagen contraction and the a-SMA expression of myofibroblasts.In conclusion, the mechanism of cytotoxicity and the in vivo safety of rhamnolipids were investigated by in vitro models, these will helpful to the pharmaceutical application of rhamnolipids. At the same time, rhamnolipids were evaluated as absorption enhancer and anti fibrosis potential drugs. |
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