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学科主题: 药学
题名:
PSA-responsive and PSMA-mediated multifunctional liposomes for targeted therapy of prostate cancer
作者: Xiang, Bai1,2; Dong, Da-Wen1; Shi, Nian-Qiu1; Gao, Wei1; Yang, Zhen-Zhen1; Cui, Yi1; Cao, De-Ying2; Qi, Xian-Rong1
关键词: Prostate cancer ; Prostate-specific antigen ; Prostate-specific membrane antigen ; Tumor microenvironment stimulus-responsive liposomes ; Cell-penetrating peptide ; Small interfering RNA
刊名: BIOMATERIALS
发表日期: 2013-09-01
DOI: 10.1016/j.biomaterials.2013.05.055
卷: 34, 期:28, 页:6976-6991
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]: CELL-PENETRATING PEPTIDES ; APTAMER-SIRNA CHIMERAS ; SMALL INTERFERING RNA ; MEMBRANE ANTIGEN ; IN-VIVO ; CARGO DELIVERY ; DRUG-DELIVERY ; TUMOR-CELLS ; FOLATE ; NANOPARTICLES
英文摘要:

In the hormone-refractory stage of prostate cancer (PC), the expression of prostate-specific antigen (PSA) and prostate-specific membrane antigen (PSMA) often remains highly active. Accumulating studies have demonstrated that these two proteins are attractive targets for specific delivery of functional molecules to advanced PC, not merely as potential sensitive markers for PC detection. In this study, we constructed a dual-modified liposome that incorporated PSA-responsive and PSMA-mediated liposomes and potentially offers double selectivity for PC. The folate moiety binds quickly to PSMA-positive tumors, and the PSA-responsive moiety is cleaved by PSA that was enriched in tumor tissues. The activated liposomes (folate and cell-penetrating peptides dual-modifications) are subsequently taken up by the tumor cells via polyarginine′s penetrating effects and receptor-mediated endocytosis. To corroborate these assumptions, a series of experiments were conducted, including PSA-responsive peptide hydrolysis kinetics, cellular uptake, internalization mechanism and escape from endosomes in PC-3 and/or 22Rv1 cells, biodistribution and antitumor activity of siRNA-loaded liposomes after systemic administration, gene silencing and cell apoptosis in vitro and in vivo. The results reveal that multivalent interactions play a key role in enhancing PC cell recognition and uptake while reducing nonspecific uptake. The dual-modified liposomes carrying small interfering RNA (siRNA) have significant advantages over the control liposomes, including single-modified (folate, CPP, PSA-responsive only) and non-modified liposomes. The dual-modified liposomes elevated cellular uptake, downregulated expression of polo-like kinase 1 (PLK-1) and augmented cell apoptosis in prostate tumor cells. The entry of the dual-modified liposomes into 22Rv1 cells occurred via multiple endocytic pathways, including clathrin-mediated endocytosis and macropinocytosis, followed by an effective endosomal escape of the entrapped siRNA into the cytoplasm. In vivo studies conducted on a 22Rv1 xenograft murine model demonstrated that the dual-modified liposomes demonstrated the maximized accumulation, retention and knockdown of PLK-1 in tumor cells, as well as the strongest inhibition of tumor growth and induction of tumor cell apoptosis. In terms of targeting capacity and therapeutic potency, the combination of a PSA-responsive and PSMA-mediated liposome presents a promising platform for therapy and diagnosis of PSMA/PSA-positive PC. (C) 2013 Elsevier Ltd. All rights reserved.

语种: 英语
所属项目编号: 30970785 ; 81273454 ; 7132113 ; 2013CB932501 ; 2009CB930303 ; 20100001110056 ; BMU20110263 ; 2011206073
项目资助者: NSFC ; Beijing NSF ; National Basic Research Program ; Ministry of Education ; Innovation Team of Ministry of Education ; Hebei NSF
WOS记录号: WOS:000322049200042
Citation statistics:
内容类型: 期刊论文
URI标识: http://ir.bjmu.edu.cn/handle/400002259/60177
Appears in Collections:北京大学药学院_期刊论文

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作者单位: 1.Peking Univ, Sch Pharmaceut Sci, State Key Lab Nat & Biomimet Drugs, Beijing 100191, Peoples R China
2.Hebei Med Univ, Sch Pharmaceut Sci, Dept Pharmaceut, Shijiazhuang 050017, Peoples R China

Recommended Citation:
Xiang, Bai,Dong, Da-Wen,Shi, Nian-Qiu,et al. PSA-responsive and PSMA-mediated multifunctional liposomes for targeted therapy of prostate cancer[J]. BIOMATERIALS,2013,34(28):6976-6991.
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