title: G5-PEG PAMAM dendrimer incorporating nanostructured lipid carriers enhance oral bioavailability and plasma lipid-lowering effect of probucol.
abstract: This work aimed to improve the oral bioavailability and plasma lipid-lowering effect of probucol (PB) by constructing a combined drug delivery system (CDDS) composed of nanostructured lipid carrier (NLC) and PEGylated poly(amidoamine) dendrimer (PEG-PAMAM). PEG-PAMAM with dendrimer generations of 5 (G5-PEG) or 7 (G7-PEG) were incorporated in PB-NLCs to form PB-CDDSs, PB-NLCs/G5-PEG and PB-NLCs/G7-PEG. The resultant two kinds of PB-CDDSs were characterized by particle size, zeta potential, drug encapsulation efficacy, PB release rates, and physical stability. Formulation effects of NLC and CDDS on the cellular uptake of hydrophobic drug were explored in Caco-2 cells by fluorescent Cy5 dye as a hydrophobic drug model. Furthermore, in vivo pharmacokinetics of the PB-CDDS composed of G5-PEG and PB-NLCs were investigated in a low density lipoprotein receptor knockout (LDLr-/-) mouse model, including plateau plasma PB concentrations after oral administration of multiple doses, and bioavailability after oral administration of a single dose of different PB formulations. In addition, lipid-lowering effect of PB-NLCs/G5-PEG was studied. The results indicate that both G5-PEG and G7-PEG significantly improved aqueous solubility of PB. The two PB-CDDSs exhibited similar particle size (around 150nm) as PB-NLCs, but slower PB burst release rate, higher total PB release amount, and better particle morphology and storage stability than PB-NLCs. In comparison with traditional NLC, CDDS dramatically enhanced cellular uptake of Cy5 into Caco-2 cells. In vivo results demonstrate that PB-NLCs/G5-PEG had the highest plateau plasma PB concentration and oral bioavailability, and the greatest cholesterol-lowering effect in comparison with PB suspensions and PB-NLCs. Therefore, G5-PEG incorporating NLC can be exploited as a promising drug delivery system to improve oral bioavailability and lipid-lowering effect of PB.
authors.affiliation: Peking University Institute of Cardiovascular Sciences, Peking University Health Science Center, Peking University, Beijing 100191, China; Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, China. Electronic address: ronaqi@bjmu.edu.cn.
authors.forename: Rong
authors.initials: R
authors.lastname: Qi
authors.affiliation: Peking University Institute of Cardiovascular Sciences, Peking University Health Science Center, Peking University, Beijing 100191, China; Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, China; School of pharmacy, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Yan-Zhi
authors.initials: YZ
authors.lastname: Li
authors.affiliation: Peking University Institute of Cardiovascular Sciences, Peking University Health Science Center, Peking University, Beijing 100191, China; Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, China.
authors.forename: Cong
authors.initials: C
authors.lastname: Chen
authors.affiliation: Peking University Institute of Cardiovascular Sciences, Peking University Health Science Center, Peking University, Beijing 100191, China; Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, China.
authors.forename: Yi-Ni
authors.initials: YN
authors.lastname: Cao
authors.affiliation: Peking University Institute of Cardiovascular Sciences, Peking University Health Science Center, Peking University, Beijing 100191, China; Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, China.
authors.forename: Mao-Mao
authors.initials: MM
authors.lastname: Yu
authors.affiliation: Peking University Institute of Cardiovascular Sciences, Peking University Health Science Center, Peking University, Beijing 100191, China; Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, China.
authors.forename: Lu
authors.initials: L
authors.lastname: Xu
authors.affiliation: School of pharmaceutical sciences, Peking University, Beijing 100191, China.
authors.forename: Bing
authors.initials: B
authors.lastname: He
authors.affiliation: Peking University Institute of Cardiovascular Sciences, Peking University Health Science Center, Peking University, Beijing 100191, China; Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, China.
authors.forename: Xu
authors.initials: X
authors.lastname: Jie
authors.affiliation: Peking University Institute of Cardiovascular Sciences, Peking University Health Science Center, Peking University, Beijing 100191, China; Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, China.
authors.forename: Wen-Wen
authors.initials: WW
authors.lastname: Shen
authors.affiliation: Peking University Institute of Cardiovascular Sciences, Peking University Health Science Center, Peking University, Beijing 100191, China; Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, China.
authors.forename: Yu-Nan
authors.initials: YN
authors.lastname: Wang
authors.affiliation: Department of Chemistry, University of Michigan, Ann Arbor, MI 48109-1055, USA.
authors.forename: Mallory A
authors.initials: MA
authors.lastname: van Dongen
authors.affiliation: Peking University Institute of Cardiovascular Sciences, Peking University Health Science Center, Peking University, Beijing 100191, China; Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, China.
authors.forename: Guo-Qing
authors.initials: GQ
authors.lastname: Liu
authors.affiliation: Department of Chemistry, University of Michigan, Ann Arbor, MI 48109-1055, USA.
authors.forename: Mark M
authors.initials: MM
authors.lastname: Banaszak Holl
authors.affiliation: School of pharmaceutical sciences, Peking University, Beijing 100191, China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: School of pharmacy, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Xue
authors.initials: X
authors.lastname: Ke
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000924:Anticholesteremic Agents / Q000008:administration & dosage* / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics; D001682:Biological Availability; D018938:Caco-2 Cells; D050091:Dendrimers / Q000008:administration & dosage* / Q000737:chemistry; D004337:Drug Carriers / Q000008:administration & dosage* / Q000737:chemistry; D065546:Drug Liberation; D006801:Humans; D008055:Lipids / Q000097:blood / Q000737:chemistry; D008297:Male; D018345:Mice, Knockout; D049329:Nanostructures / Q000008:administration & dosage* / Q000737:chemistry; D011092:Polyethylene Glycols / Q000008:administration & dosage* / Q000737:chemistry; D011341:Probucol / Q000008:administration & dosage* / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics; D011973:Receptors, LDL / Q000235:genetics
chemical_list: D000924:Anticholesteremic Agents; D050091:Dendrimers; D004337:Drug Carriers; D008055:Lipids; C522249:PEG-PAMAM; D011973:Receptors, LDL; D011092:Polyethylene Glycols; D011341:Probucol
keywords: Lipid-lowering effect; Nanostructured lipid carriers; Oral bioavailability; PEG-PAMAM dendrimers; Probucol; Water solubility