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Chemotherapeutic drug delivery to cancer cells using a combination of folate targeting and tumor microenvironment-sensitive polypeptides
Gao, Wei1; Xiang, Bai1; Meng, Ting-Ting1; Liu, Feng2; Qi, Xian-Rong1
关键词Tumor microenvironment-sensitive polypeptides (TMSP) Folate Nanostructured lipid carrier (NLC) Cell-penetrating peptides Cancer-targeted therapy Docetaxel
刊名BIOMATERIALS
2013-05-01
DOI10.1016/j.biomaterials.2013.02.014
34期:16页:4137-4149
收录类别SCI
文章类型Article
WOS标题词Science & Technology
类目[WOS]Engineering, Biomedical ; Materials Science, Biomaterials
研究领域[WOS]Engineering ; Materials Science
关键词[WOS]CELLULAR UPTAKE ; ANTITUMOR EFFICACY ; PROSTATE-CANCER ; IN-VITRO ; DOCETAXEL ; LIPOSOMES ; RECEPTOR ; CONJUGATE ; THERAPY ; NANOPARTICLES
英文摘要

Chemotherapeutic agents often cause severe side effects because they produce a similar cytotoxicity in both cancerous and healthy cells. In this study, a rational strategy was implemented to take advantage of a combination of both tumor microenvironment-sensitive polypeptides (TMSP) and folate to create a more selective and efficient drug delivery system to target cancer cells. TMSP and folate were conjugated to the distal ends of DSPE-PEG(2000)-maleimide and DSPE-PEG(5000)-amine to create DSPE-PEG(2000)-TMSP and DSPE-PEG(5000)-folate, respectively, which were incorporated onto the surface of a docetaxel-loaded nanostructured lipid carrier (F/TMSP-DTX-NLC). TMSP are comprised of polycationic cell-penetrating peptides (CPP) and polyanionic inhibitory peptides, which are coupled via a proteinase-sensitive cleavable linker. The linker can be cleaved in the presence of matrix metalloprotease-2 and -9 (MMP-2/9). TMSP provides the ability to enhance specific cancer cellular uptake after selectively unmasking polyanionic inhibitory peptides in MMP-2/9 protease-oversecretion tumor tissue, whereas in circulation, the penetration is shielded. The folate moiety binds selectively to folate receptor-positive tumors. The cleaved dual-modified nanocarriers are then taken up by the tumor cells via both receptor-mediated endocytosis and CPP penetrating action to overcome the higher interstitial pressure in the tumor. The nanocarrier system demonstrated a small size, high encapsulation efficiency (>95%), sustained release and targeted delivery. The strong cellular uptake and cytotoxic activity of dual-modified F/TMSP-DTX-NLC in KB, HT-1080, MCF-7 and A549 cells verified the correlation with folate receptor expression and MMP-2/9 secretion. The remarkable penetration into KB and HT-1080 multicellular tumor spheroids confirmed that the temporary mask of the polyanionic inhibitory peptide in TMSP does not disturb the penetration ability of CPP in the tumor microenvironment with abundant proteases. Furthermore, the active targeting and triggered activation exhibited higher antitumor efficacy and lower systemic toxicity with the KB tumor model in nude mice compared to the nonmodified DTX-NLC and Taxotere (R). These results suggested that the application of combined TMSP and folate modifications may be an approach in the selectively targeted delivery of anticancer drugs with low systemic toxicity. (C) 2013 Elsevier Ltd. All rights reserved.

语种英语
WOS记录号WOS:000317322600021
项目编号30970785 ; 81273454 ; 7132113 ; 2009CB930303 ; 2013CB932501 ; 20100001110056 ; BMU20110263
资助机构NSFC ; Beijing NSF ; National Basic Research Program ; Doctoral Foundation of the Ministry of Education ; Innovation Team of Ministry of Education
引用统计
被引频次:123[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/400002259/58347
专题北京大学药学院
北京大学药学院_药剂学系
北京大学第三临床医学院_心血管内科
作者单位1.Peking Univ, Sch Pharmaceut Sci, State Key Lab Nat & Biomimet Drugs, Beijing 100191, Peoples R China
2.Univ N Carolina, Sch Pharm, Div Mol Pharmaceut, Chapel Hill, NC 27599 USA
推荐引用方式
GB/T 7714
Gao, Wei,Xiang, Bai,Meng, Ting-Ting,et al. Chemotherapeutic drug delivery to cancer cells using a combination of folate targeting and tumor microenvironment-sensitive polypeptides[J]. BIOMATERIALS,2013,34(16):4137-4149.
APA Gao, Wei,Xiang, Bai,Meng, Ting-Ting,Liu, Feng,&Qi, Xian-Rong.(2013).Chemotherapeutic drug delivery to cancer cells using a combination of folate targeting and tumor microenvironment-sensitive polypeptides.BIOMATERIALS,34(16),4137-4149.
MLA Gao, Wei,et al."Chemotherapeutic drug delivery to cancer cells using a combination of folate targeting and tumor microenvironment-sensitive polypeptides".BIOMATERIALS 34.16(2013):4137-4149.
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