title: Systemic and tumor-targeted delivery of siRNA by cyclic NGR and isoDGR motif-containing peptides.
abstract: The drug development of siRNA has been seriously hindered by the lack of an effective, safe and clinically applicable delivery system. The cyclic NGR motif and its isomerization product isoDGR recruit CD13 and integrin as their specific receptors, both of which are overexpressed by tumor and neovascular cells. In this study, a bi-functional peptide, named NGR-10R, was designed and tested for siRNA delivery in vitro and in vivo. Through the formation of peptide/siRNA nanoparticles, RNase resistance was greatly enhanced for the siRNAs. Both FACS and confocal assays revealed that the peptide/siRNA complexes were effectively internalized by MDA-MB-231 cells. Gene silencing assays indicated that anti-Lamin A/C siRNA delivered by NGR-10R robustly repressed gene expression in MDA-MB-231 and HUVEC (a CD13(+)/αvβ3(+) cell). Importantly, the siRNAs were efficiently delivered into tumor tissues and localized around the nuclei, as revealed by in vivo imaging and cryosection examination. In summary, NGR-10R not only efficiently delivered siRNAs into MDA-MB-231 cells in vitro but also delivered siRNAs into tumor cells in vivo, taking advantage of its specific binding to CD13 (neovascular) or αvβ3 (MDA-MB-231). Therefore, the NGR-10R peptide provides a promising siRNA delivery reagent that could be used for drug development, particularly for anti-tumor therapeutics.
authors.affiliation: Institute of Molecular Medicine, State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100871, China. yyhuang@pku.edu.cn liangz@pku.edu.cn quan.du@pku.edu.cn.
authors.forename: Yuanyu
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Institute of Molecular Medicine, State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100871, China. yyhuang@pku.edu.cn liangz@pku.edu.cn quan.du@pku.edu.cn.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Cheng
authors.affiliation: Suzhou Ribo Life Science Co. Ltd, Jiangsu 215300, China.
authors.forename: Xingyu
authors.initials: X
authors.lastname: Jin
authors.affiliation: Suzhou Ribo Life Science Co. Ltd, Jiangsu 215300, China.
authors.forename: Jia-Li
authors.initials: JL
authors.lastname: Ji
authors.affiliation: Chinese Academy of Sciences Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology of China, Beijing 100190, China.
authors.forename: Shutao
authors.initials: S
authors.lastname: Guo
authors.affiliation: Institute of Molecular Medicine, State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100871, China. yyhuang@pku.edu.cn liangz@pku.edu.cn quan.du@pku.edu.cn.
authors.forename: Shuquan
authors.initials: S
authors.lastname: Zheng
authors.affiliation: Institute of Molecular Medicine, State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100871, China. yyhuang@pku.edu.cn liangz@pku.edu.cn quan.du@pku.edu.cn.
authors.forename: Xiaoxia
authors.initials: X
authors.lastname: Wang
authors.affiliation: Institute of Molecular Medicine, State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100871, China. yyhuang@pku.edu.cn liangz@pku.edu.cn quan.du@pku.edu.cn.
authors.forename: Huiqing
authors.initials: H
authors.lastname: Cao
authors.affiliation: Suzhou Ribo Life Science Co. Ltd, Jiangsu 215300, China.
authors.forename: Shan
authors.initials: S
authors.lastname: Gao
authors.affiliation: Chinese Academy of Sciences Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology of China, Beijing 100190, China.
authors.forename: Xing-Jie
authors.initials: XJ
authors.lastname: Liang
authors.affiliation: Institute of Molecular Medicine, State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100871, China. yyhuang@pku.edu.cn liangz@pku.edu.cn quan.du@pku.edu.cn.
authors.forename: Quan
authors.initials: Q
authors.lastname: Du
authors.affiliation: Institute of Molecular Medicine, State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100871, China. yyhuang@pku.edu.cn liangz@pku.edu.cn quan.du@pku.edu.cn and Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin 300072, China.
authors.forename: Zicai
authors.initials: Z
authors.lastname: Liang
mesh_terms: D018826:CD13 Antigens / Q000737:chemistry* / Q000378:metabolism; D045744:Cell Line, Tumor; D020868:Gene Silencing; D061307:Human Umbilical Vein Endothelial Cells / Q000737:chemistry*; D006801:Humans; D016023:Integrins / Q000737:chemistry / Q000378:metabolism; D053758:Nanoparticles / Q000737:chemistry*; D009842:Oligopeptides / Q000737:chemistry* / Q000378:metabolism; D010455:Peptides / Q000737:chemistry* / Q000378:metabolism; D034741:RNA, Small Interfering / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D016023:Integrins; C526428:NGR peptide; D009842:Oligopeptides; D010455:Peptides; D034741:RNA, Small Interfering; D018826:CD13 Antigens