title: Oral absorption enhancement of probucol by PEGylated G5 PAMAM dendrimer modified nanoliposomes.
abstract: Probucol (PB), an antioxidant drug, is commonly used as a lipid concentration lowering drug to reduce blood plasma cholesterol levels in the clinic. However, the therapeutic effects of this drug are negatively impacted by its poor water solubility and low oral absorption efficiency. In this study, a PEGylated G5 PAMAM dendrimer (G5-PEG) modified nanoliposome was employed to increase water solubility, transepithelial transport, and oral absorption of PB. The uptake mechanism was explored in vitro in Caco-2 cells with the results suggesting that the absorption improvement of G5-PEG modified PB-liposome (PB-liposome/G5-PEG) was related to P-glycoprotein (P-gp) efflux pump but was independent of caveolae endocytosis pathways. Additionally, plasma lipid concentration lowering effects of PB-liposome/G5-PEG were evaluated in vivo in a LDLR-/- hyperlipidemia mouse model. Compared with saline treated group, treatment with PB-liposome/G5-PEG significantly inhibited the increase of plasma total cholesterol (TC) and triglyceride (TG) of mice induced by a high fat diet. Moreover, its lipid concentration lowering effects and plasma drug concentration were greater than PB alone or commercial PB tablets. Our results demonstrated that PB-liposome/G5-PEG significantly increased the oral absorption of PB and therefore significantly improved its pharmacodynamic effects.
authors.affiliation: Peking University Institute of Cardiovascular Sciences, Peking University Health Science Center, Peking University , Beijing 100191, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Ma
authors.forename: Yingchun
authors.initials: Y
authors.lastname: Han
authors.forename: Cong
authors.initials: C
authors.lastname: Chen
authors.forename: Yini
authors.initials: Y
authors.lastname: Cao
authors.forename: Siling
authors.initials: S
authors.lastname: Wang
authors.forename: Wenwen
authors.initials: W
authors.lastname: Shen
authors.forename: Huayu
authors.initials: H
authors.lastname: Zhang
authors.forename: Yanzhi
authors.initials: Y
authors.lastname: Li
authors.forename: Mallory A
authors.initials: MA
authors.lastname: van Dongen
authors.forename: Bing
authors.initials: B
authors.lastname: He
authors.forename: Maomao
authors.initials: M
authors.lastname: Yu
authors.forename: Lu
authors.initials: L
authors.lastname: Xu
authors.forename: Mark M
authors.initials: MM
authors.lastname: Banaszak Holl
authors.forename: George
authors.initials: G
authors.lastname: Liu
authors.forename: Qiang
authors.initials: Q
authors.lastname: Zhang
authors.forename: Rong
authors.initials: R
authors.lastname: Qi
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000924:Anticholesteremic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D018938:Caco-2 Cells; D002784:Cholesterol / Q000097:blood; D050091:Dendrimers / Q000737:chemistry; D016503:Drug Delivery Systems; D004355:Drug Stability; D006801:Humans; D006949:Hyperlipidemias / Q000097:blood / Q000188:drug therapy; D007408:Intestinal Absorption; D008081:Liposomes / Q000737:chemistry; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D053769:Nanocapsules / Q000737:chemistry; D011092:Polyethylene Glycols / Q000737:chemistry; D011341:Probucol / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics; D012995:Solubility; D014280:Triglycerides / Q000097:blood
chemical_list: D000924:Anticholesteremic Agents; D050091:Dendrimers; D008081:Liposomes; D053769:Nanocapsules; C104700:PAMAM Starburst; D011973:Receptors, LDL; D014280:Triglycerides; D011092:Polyethylene Glycols; D002784:Cholesterol; D011341:Probucol
keywords: G5-PEG PAMAM dendrimer; in vivo pharmacodynamic effects; nanoliposome; probucol; transepithelial absorption and mechanism