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 language | English |
|---|---|
| Pages (from-to) | 665-674 |
| Number of pages | 10 |
| Journal | Molecular Pharmaceutics |
| Volume | 12 |
| Issue number | 3 |
| DOIs | |
| Publication status | Published - 2 Mar 2015 |
| Externally published | Yes |
Keywords
- G5-PEG PAMAM dendrimer
- in vivo pharmacodynamic effects
- nanoliposome
- probucol
- transepithelial absorption and mechanism
Cite this
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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 journal › Article › Research › peer-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).
KW - G5-PEG PAMAM dendrimer
KW - in vivo pharmacodynamic effects
KW - nanoliposome
KW - probucol
KW - transepithelial absorption and mechanism
UR - http://www.scopus.com/inward/record.url?scp=84924362935&partnerID=8YFLogxK
U2 - 10.1021/mp500388m
DO - 10.1021/mp500388m
M3 - Article
VL - 12
SP - 665
EP - 674
JO - Molecular Pharmaceutics
JF - Molecular Pharmaceutics
SN - 1543-8384
IS - 3
ER -