title: Enhanced oral absorption of insulin-loaded liposomes containing bile salts: a mechanistic study.
abstract: Liposomes containing bile salts (BS-liposomes) significantly enhanced the oral bioavailability of insulin (rhINS). However, the underlying absorption mechanisms have not been well understood yet. In this study, the transiting fate of the liposomes was first investigated using fluorescent imaging tools to confirm the effect of enhanced gastrointestinal stability. In order to obtain evidence of enhanced transcellular permeation, the interaction between BS-liposomes and the biomembrane was investigated in Caco-2 cell lines. BS-liposomes were found to be more stable in the gastrointestinal tract by showing prolonged residence time in comparison with conventional liposomes. BS-liposomes were significantly more effective for cellular uptake and transport of rhINS; and this effect was found to be size- and concentration-dependent. A good linear correlation was observed between the concentration of the liposomes and uptake/transport of rhINS. Confocal laser scanning microscopy visualization further validated the transcellular transit of BS-liposomes. The BS-liposomes showed little effect on cytotoxicity and did not induce apoptosis within 24h investigation. It was concluded that BS-liposomes showed improved in vivo residence time and enhanced permeation across the biomemebranes. Mechanisms of trans-enterocytic internalization could be proposed as an interpretation for enhanced absorption of insulin-loaded liposomes.
authors.affiliation: School of Pharmacy, Fudan University, Shanghai 201203, PR China.
authors.forename: Mengmeng
authors.initials: M
authors.lastname: Niu
authors.affiliation: School of Pharmacy, Fudan University, Shanghai 201203, PR China.
authors.forename: Ya'nan
authors.initials: Y
authors.lastname: Tan
authors.affiliation: School of Pharmacy, Fudan University, Shanghai 201203, PR China.
authors.forename: Peipei
authors.initials: P
authors.lastname: Guan
authors.affiliation: Oral Formulation Development, Novo Nordisk A/S, DK-2760 Maalov, Denmark.
authors.forename: Lars
authors.initials: L
authors.lastname: Hovgaard
authors.affiliation: School of Pharmacy, Fudan University, Shanghai 201203, PR China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Lu
authors.affiliation: School of Pharmacy, Fudan University, Shanghai 201203, PR China.
authors.forename: Jianping
authors.initials: J
authors.lastname: Qi
authors.affiliation: School of Pharmacy, Fudan University, Shanghai 201203, PR China.
authors.forename: Ruyue
authors.initials: R
authors.lastname: Lian
authors.affiliation: School of Pharmacy, Fudan University, Shanghai 201203, PR China.
authors.forename: Xiaoyang
authors.initials: X
authors.lastname: Li
authors.affiliation: School of Pharmacy, Fudan University, Shanghai 201203, PR China. Electronic address: wuwei@shmu.edu.cn.
authors.forename: Wei
authors.initials: W
authors.lastname: Wu
mesh_terms: D000284:Administration, Oral; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001647:Bile Acids and Salts / Q000737:chemistry; D018938:Caco-2 Cells; D002470:Cell Survival / Q000187:drug effects; D041981:Gastrointestinal Tract / Q000378:metabolism*; D006801:Humans; D007328:Insulin / Q000008:administration & dosage / Q000493:pharmacokinetics*; D007408:Intestinal Absorption; D008081:Liposomes; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000493:pharmacokinetics*
chemical_list: D001647:Bile Acids and Salts; D007328:Insulin; D008081:Liposomes; D011994:Recombinant Proteins
keywords: Bile salt; Cellular uptake; Cytotoxicity; Insulin; Liposomes; Transport