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Cleavable Multifunctional Targeting Mixed Micelles with Sequential pH-Triggered TAT Peptide Activation for Improved Antihepatocellular Carcinoma Efficacy
Zhang, Jinming1; Zheng, Yifeng2; Xie, Xi3; Wang, Lan2; Su, Ziren2; Wang, Yitao1; Leong, Kam W.4; Chen, Meiwan1
2017-11
Source PublicationMOLECULAR PHARMACEUTICS
ISSN1543-8384
Volume14Issue:11Pages:3644-3659
Abstract

Although tumor-targeting nanovehicles for hepatocellular carcinoma (HCC) chemotherapy have attracted great research and clinic interest, the poor cancer penetration, inefficient cellular uptake, and slow intracellular drug release greatly compromise their therapeutic outcomes. In this work, a multifunctional mixed micellar system, consisting of glycyrrhetinic acid (GA) for specific liver-targeting, trans-activator of transcription (TAT) peptide for potent cell penetration, and pH-sensitive poly(beta-amino ester) polymers for acidic-triggered drug release, was developed to provide HCC-targeting delivery and pH-triggered release of doxorubicin (DOX). These micelles were hypothesized to efficaciously accumulate in HCC site by the guide of GA ligands, enter into cancer cells facilitated by the activated TAT peptide on the micellar surface, and finally rapidly release DOX in cytoplasm. To demonstrate this design, DOX was initially loaded in micelles modified with both GA and TAT (DOX/GA@TAT-M) with high drug loading efficiency and pH-sensitive drug release profiles. The HCC-targeting cellular uptake and synergetic anticancer efficacy were tested, indicating DOX/GA@TAT-M could be specifically and effectively internalized into HCC cells by the effect of GA targeting and TAT penetrating with enhanced cytotoxicity. In addition, the prolonged circulation time and enhanced accumulation in tumor facilitated its potent tumor growth inhibition activity in vivo. These results demonstrated that the cleavable multifunctional mixed micelles with tumor targeting, controlled TAT peptide activation, and sequential pH-sensitive drug release could be an efficient strategy for HCC treatment.

KeywordTumor-targeting Glycyrrhetinic Acid Ph-sensitive Tat Exposure Mixed Micelles
DOIhttp://doi.org/10.1021/acs.molpharmaceut.7b00404
URLView the original
Indexed BySCI
Language英语
WOS Research AreaResearch & Experimental Medicine ; Pharmacology & Pharmacy
WOS SubjectMedicine, Research & Experimental ; Pharmacology & Pharmacy
WOS IDWOS:000414820000004
PublisherAMER CHEMICAL SOC
The Source to ArticleWOS
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Cited Times [WOS]:6   [WOS Record]     [Related Records in WOS]
Document TypeJournal article
CollectionInstitute of Chinese Medical Sciences
Corresponding AuthorSu, Ziren; Chen, Meiwan
Affiliation1.State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao 999078, China
2.College of Chinese Medicines, Guangzhou University of Chinese Medicine, Guangzhou 510006, China
3.State Key Laboratory of Optoelectronic Materials and Technologies, School of Electronics and Information Technology, Sun Yat-Sen University, Guangzhou 510275, China
4.Department of Biomedical Engineering, Columbia University, New York, New York 10027, United States
First Author AffilicationInstitute of Chinese Medical Sciences
Corresponding Author AffilicationInstitute of Chinese Medical Sciences
Recommended Citation
GB/T 7714
Zhang, Jinming,Zheng, Yifeng,Xie, Xi,et al. Cleavable Multifunctional Targeting Mixed Micelles with Sequential pH-Triggered TAT Peptide Activation for Improved Antihepatocellular Carcinoma Efficacy[J]. MOLECULAR PHARMACEUTICS,2017,14(11):3644-3659.
APA Zhang, Jinming.,Zheng, Yifeng.,Xie, Xi.,Wang, Lan.,Su, Ziren.,...&Chen, Meiwan.(2017).Cleavable Multifunctional Targeting Mixed Micelles with Sequential pH-Triggered TAT Peptide Activation for Improved Antihepatocellular Carcinoma Efficacy.MOLECULAR PHARMACEUTICS,14(11),3644-3659.
MLA Zhang, Jinming,et al."Cleavable Multifunctional Targeting Mixed Micelles with Sequential pH-Triggered TAT Peptide Activation for Improved Antihepatocellular Carcinoma Efficacy".MOLECULAR PHARMACEUTICS 14.11(2017):3644-3659.
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