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学科主题: 药学
题名:
Enhancing cellular uptake of activable cell-penetrating peptide-doxorubicin conjugate by enzymatic cleavage
作者: 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
发表日期: 2012
DOI: 10.2147/IJN.S30104
卷: 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
所属项目编号: 30772665 ; 30970785 ; 2007CB935801 ; 2009CB930300 ; 20100001110056
项目资助者: National Natural Science Foundation of China ; National Basic Research Program of China ; Doctoral Foundation of the Ministry of Education of China
WOS记录号: WOS:000302731000001
Citation statistics:
内容类型: 期刊论文
URI标识: http://ir.bjmu.edu.cn/handle/400002259/54269
Appears in Collections:北京大学药学院_药剂学系_期刊论文

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作者单位: Peking Univ, Dept Pharmaceut, Sch Pharmaceut Sci, Beijing 100191, Peoples R China

Recommended Citation:
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.
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