Oral Absorption Enhancement of Probucol by PEGylated G5 PAMAM Dendrimer Modified Nanoliposomes

Qian Ma, Yingchun Han, Cong Chen, Yini Cao, Siling Wang, Wenwen Shen, Huayu Zhang, Yanzhi Li, Mallory A. van Dongen, Bing He, Maomao Yu, Lu Xu, Mark M. Banaszak Holl, George Liu, Qiang Zhang, Rong Qi

Research output: Contribution to journalArticleResearchpeer-review

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. (Graph Presented).

Original languageEnglish
Pages (from-to)665-674
Number of pages10
JournalMolecular Pharmaceutics
Volume12
Issue number3
DOIs
Publication statusPublished - 2 Mar 2015
Externally publishedYes

Keywords

  • G5-PEG PAMAM dendrimer
  • in vivo pharmacodynamic effects
  • nanoliposome
  • probucol
  • transepithelial absorption and mechanism

Cite this

Ma, Qian ; Han, Yingchun ; Chen, Cong ; Cao, Yini ; Wang, Siling ; Shen, Wenwen ; Zhang, Huayu ; Li, Yanzhi ; van Dongen, Mallory A. ; He, Bing ; Yu, Maomao ; Xu, Lu ; Banaszak Holl, Mark M. ; Liu, George ; Zhang, Qiang ; Qi, Rong. / Oral Absorption Enhancement of Probucol by PEGylated G5 PAMAM Dendrimer Modified Nanoliposomes. In: Molecular Pharmaceutics. 2015 ; Vol. 12, No. 3. pp. 665-674.
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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. (Graph Presented).",
keywords = "G5-PEG PAMAM dendrimer, in vivo pharmacodynamic effects, nanoliposome, probucol, transepithelial absorption and mechanism",
author = "Qian Ma and Yingchun Han and Cong Chen and Yini Cao and Siling Wang and Wenwen Shen and Huayu Zhang and Yanzhi Li and {van Dongen}, {Mallory A.} and Bing He and Maomao Yu and Lu Xu and {Banaszak Holl}, {Mark M.} and George Liu and Qiang Zhang and Rong Qi",
year = "2015",
month = "3",
day = "2",
doi = "10.1021/mp500388m",
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Ma, Q, Han, Y, Chen, C, Cao, Y, Wang, S, Shen, W, Zhang, H, Li, Y, van Dongen, MA, He, B, Yu, M, Xu, L, Banaszak Holl, MM, Liu, G, Zhang, Q & Qi, R 2015, 'Oral Absorption Enhancement of Probucol by PEGylated G5 PAMAM Dendrimer Modified Nanoliposomes' Molecular Pharmaceutics, vol. 12, no. 3, pp. 665-674. https://doi.org/10.1021/mp500388m

Oral Absorption Enhancement of Probucol by PEGylated G5 PAMAM Dendrimer Modified Nanoliposomes. / Ma, Qian; Han, Yingchun; Chen, Cong; Cao, Yini; Wang, Siling; Shen, Wenwen; Zhang, Huayu; Li, Yanzhi; van Dongen, Mallory A.; He, Bing; Yu, Maomao; Xu, Lu; Banaszak Holl, Mark M.; Liu, George; Zhang, Qiang; Qi, Rong.

In: Molecular Pharmaceutics, Vol. 12, No. 3, 02.03.2015, p. 665-674.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Oral Absorption Enhancement of Probucol by PEGylated G5 PAMAM Dendrimer Modified Nanoliposomes

AU - Ma, Qian

AU - Han, Yingchun

AU - Chen, Cong

AU - Cao, Yini

AU - Wang, Siling

AU - Shen, Wenwen

AU - Zhang, Huayu

AU - Li, Yanzhi

AU - van Dongen, Mallory A.

AU - He, Bing

AU - Yu, Maomao

AU - Xu, Lu

AU - Banaszak Holl, Mark M.

AU - Liu, George

AU - Zhang, Qiang

AU - Qi, Rong

PY - 2015/3/2

Y1 - 2015/3/2

N2 - 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. (Graph Presented).

AB - 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. (Graph Presented).

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KW - in vivo pharmacodynamic effects

KW - nanoliposome

KW - probucol

KW - transepithelial absorption and mechanism

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