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PSA-responsive and PSMA-mediated multifunctional liposomes for targeted therapy of prostate cancer
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
2013-09-01
DOI10.1016/j.biomaterials.2013.05.055
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
WOS记录号WOS:000322049200042
项目编号30970785 ; 81273454 ; 7132113 ; 2013CB932501 ; 2009CB930303 ; 20100001110056 ; BMU20110263 ; 2011206073
资助机构NSFC ; Beijing NSF ; National Basic Research Program ; Ministry of Education ; Innovation Team of Ministry of Education ; Hebei NSF
引用统计
被引频次:70[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/400002259/60177
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.Hebei Med Univ, Sch Pharmaceut Sci, Dept Pharmaceut, Shijiazhuang 050017, Peoples R China
推荐引用方式
GB/T 7714
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.
APA Xiang, Bai.,Dong, Da-Wen.,Shi, Nian-Qiu.,Gao, Wei.,Yang, Zhen-Zhen.,...&Qi, Xian-Rong.(2013).PSA-responsive and PSMA-mediated multifunctional liposomes for targeted therapy of prostate cancer.BIOMATERIALS,34(28),6976-6991.
MLA Xiang, Bai,et al."PSA-responsive and PSMA-mediated multifunctional liposomes for targeted therapy of prostate cancer".BIOMATERIALS 34.28(2013):6976-6991.
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