Liposomes coated with N-trimethyl chitosan to improve the absorption of harmine in vivo and in vitro

• Published in: International journal of nanomedicine 2016-01, Vol.11 (Issue 1), p.325-336
• Main Authors: Chen, Wei-Liang, Yuan, Zhi-Qiang, Liu, Yang, Yang, Shu-di, Zhang, Chun-ge, Li, Ji-Zhao, Zhu, Wen-jing, Li, Fang, Zhou, Xiao-feng, Lin, Yi-mei, Zhang, Xue-nong
• Format: Article
• Language: English
• Subjects: Administration, Oral; Animals; bioavailability; Biological Availability; Caco-2 cell; Caco-2 Cells; Cell Membrane Permeability; Cell Proliferation - drug effects; Cells, Cultured; Chitosan - chemistry; Drug Carriers - chemistry; Gastrointestinal system; Gastrointestinal Tract - cytology; Gastrointestinal Tract - drug effects; Gastrointestinal Tract - metabolism; harmine; Harmine - metabolism; High performance liquid chromatography; Humans; In Vitro Techniques; liposomes; Liposomes - administration & dosage; Liposomes - chemistry; Mice; Original Research; Particle Size; Rats; Rats, Sprague-Dawley; Thin films; TMC
• ISSN: 1178-2013; 1176-9114; 1178-2013
• DOI: 10.2147/IJN.S95540

In this study, harmine liposomes (HM-lip) were prepared through the thin-film hydration-pH-gradient method and then coated with N-trimethyl chitosan (TMC). Particle size, zeta potential, entrapment efficiency, and in vitro release of HM-lip and TMC-coated harmine liposomes (TMC-HM-lip) were also determined. Sprague Dawley rats were further used to investigate the pharmacokinetics in vivo. Retention behavior in mouse gastrointestinal tract (GIT) was studied through high-performance liquid chromatography and near-infrared imaging. Degradation was further evaluated through incubation with Caco-2 cell homogenates, and a Caco-2 monolayer cell model was used to investigate the uptake and transport of drugs. HM-lip and TMC-HM-lip with particle size of 150-170 nm, an entrapment efficiency of about 81%, and a zeta potential of negative and positive, respectively, were prepared. The release of HM from HM-lip and TMC-HM-lip was slower than that from HM solution and was sensitive to pH. TMC-HM-lip exhibited higher oral bioavailability and had prolonged retention time in GIT. HM-lip and TMC-HM-lip could also protect HM against degradation in Caco-2 cell homogenates. The uptake amount of TMC-HM-lip was higher than that of HM and HM-lip. TMC-HM-lip further demonstrated higher apparent permeability coefficient (P(app)) from the apical to the basolateral side than HM and HM-lip because of its higher uptake and capability to open tight junctions in the cell monolayers. TMC-HM-lip can prolong the retention time in the GIT, protect HM against enzyme degradation, and improve transport across Caco-2 cell monolayers, thus enhancing the oral bioavailability of HM.