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Enhancing cellular uptake of activable cell-penetrating peptide-doxorubicin conjugate by enzymatic cleavage
Shi, Nian-Qiu; Gao, Wei; Xiang, Bai; Qi, Xian-Rong
关键词Activable Cell-penetrating Peptide Matrix Metalloproteinase Proteinase-sensitive Substrate Cellular Uptake Antiproliferative Enzymatic Cleavage Tumor Extracellular Environment
刊名INTERNATIONAL JOURNAL OF NANOMEDICINE
2012
DOI10.2147/IJN.S30104
7页:1613-1621
收录类别SCI
文章类型Article
WOS标题词Science & Technology
类目[WOS]Nanoscience & Nanotechnology ; Pharmacology & Pharmacy
研究领域[WOS]Science & Technology - Other Topics ; Pharmacology & Pharmacy
关键词[WOS]MULTIDRUG-RESISTANCE ; CANCER-CELLS ; TUMOR-CELLS ; DELIVERY ; NANOPARTICLES ; FLUORESCENCE ; ACTIVATION ; TRANSPORTERS ; EXPRESSION ; LIPOSOMES
英文摘要

The use of activable cell-penetrating peptides (ACPPs) as molecular imaging probes is a promising new approach for the visualization of enzymes. The cell-penetrating function of a polycationic cell-penetrating peptide (CPP) is efficiently blocked by intramolecular electrostatic interactions with a polyanionic peptide. Proteolysis of a proteinase-sensitive substrate present between the CPP and polyanionic peptide affords dissociation of both domains and enables the activated CPP to enter cells. This ACPP strategy could also be used to modify antitumor agents for tumor-targeting therapy. Here, we aimed to develop a conjugate of ACPP with antitumor drug doxorubicin (DOX) sensitive to matrix metalloproteinase-2 and -9 (MMP-2/9) for tumor-targeting therapy purposes. The ACPP-DOX conjugate was successfully synthesized. Enzymatic cleavage of ACPP-DOX conjugate by matrix metalloproteinase (MMP)-2/9 indicated that the activation of ACPP-DOX occurred in an enzyme concentration-dependent manner. Flow cytometry and laser confocal microscope studies revealed that the cellular uptake of ACPP-DOX was enhanced after enzymatic-triggered activation and was higher in HT-1080 cells (overexpressed MMPs) than in MCF-7 cells (under-expressed MMPs). The antiproliferative assay showed that ACPP had little toxicity and that ACPP-DOX effectively inhibited HT-1080 cell proliferation. These experiments revealed that the ACPP-DOX conjugate could be triggered by MMP-2/9, which enabled the activated CPP-DOX to enter cells. ACPP-DOX conjugate may be a potential prodrug delivery system used to carry antitumor drugs for MMP-related tumor therapy.

语种英语
WOS记录号WOS:000302731000001
项目编号30772665 ; 30970785 ; 2007CB935801 ; 2009CB930300 ; 20100001110056
资助机构National Natural Science Foundation of China ; National Basic Research Program of China ; Doctoral Foundation of the Ministry of Education of China
引用统计
被引频次:63[WOS]   [WOS记录]     [WOS相关记录]
文献类型期刊论文
条目标识符http://ir.bjmu.edu.cn/handle/400002259/54269
专题北京大学第三临床医学院_心血管内科
北京大学药学院_药剂学系
作者单位Peking Univ, Dept Pharmaceut, Sch Pharmaceut Sci, Beijing 100191, Peoples R China
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GB/T 7714
Shi, Nian-Qiu,Gao, Wei,Xiang, Bai,et al. Enhancing cellular uptake of activable cell-penetrating peptide-doxorubicin conjugate by enzymatic cleavage[J]. INTERNATIONAL JOURNAL OF NANOMEDICINE,2012,7:1613-1621.
APA Shi, Nian-Qiu,Gao, Wei,Xiang, Bai,&Qi, Xian-Rong.(2012).Enhancing cellular uptake of activable cell-penetrating peptide-doxorubicin conjugate by enzymatic cleavage.INTERNATIONAL JOURNAL OF NANOMEDICINE,7,1613-1621.
MLA Shi, Nian-Qiu,et al."Enhancing cellular uptake of activable cell-penetrating peptide-doxorubicin conjugate by enzymatic cleavage".INTERNATIONAL JOURNAL OF NANOMEDICINE 7(2012):1613-1621.
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