title: Targeted delivery of PLK1-siRNA by ScFv suppresses Her2+ breast cancer growth and metastasis.
abstract: A major obstacle to developing small interfering RNAs (siRNAs) as cancer drugs is their intracellular delivery to disseminated cancer cells. Fusion proteins of single-chain fragmented antibodies (ScFvs) and positively charged peptides deliver siRNAs into specific target cells. However, the therapeutic potential of ScFv-mediated siRNA delivery has not been evaluated in cancer. Here, we tested whether Polo-like kinase 1 (PLK1) siRNAs complexed with a Her2-ScFv-protamine peptide fusion protein (F5-P) could suppress Her2(+) breast cancer cell lines and primary human cancers in orthotopic breast cancer models. PLK1-siRNAs transferred by F5-P inhibited target gene expression, reduced proliferation, and induced apoptosis of Her2(+) breast cancer cell lines and primary human cancer cells in vitro without triggering an interferon response. Intravenously injected F5-P/PLK1-siRNA complexes concentrated in orthotopic Her2(+) breast cancer xenografts and persisted for at least 72 hours, leading to suppressed PLK1 gene expression and tumor cell apoptosis. The intravenously injected siRNA complexes retarded Her2(+) breast tumor growth, reduced metastasis, and prolonged survival without evident toxicity. F5-P-mediated delivery of a cocktail of PLK1, CCND1, and AKT siRNAs was more effective than an equivalent dose of PLK1-siRNAs alone. These data suggest that F5-P could be used to deliver siRNAs to treat Her2(+) breast cancer.
authors.affiliation: Breast Tumor Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China.
authors.forename: Yan-dan
authors.initials: YD
authors.lastname: Yao
authors.forename: Tian-meng
authors.initials: TM
authors.lastname: Sun
authors.forename: Song-yin
authors.initials: SY
authors.lastname: Huang
authors.forename: Shuang
authors.initials: S
authors.lastname: Dou
authors.forename: Ling
authors.initials: L
authors.lastname: Lin
authors.forename: Jia-ning
authors.initials: JN
authors.lastname: Chen
authors.forename: Jian-bin
authors.initials: JB
authors.lastname: Ruan
authors.forename: Cheng-qiong
authors.initials: CQ
authors.lastname: Mao
authors.forename: Feng-yan
authors.initials: FY
authors.lastname: Yu
authors.forename: Mu-sheng
authors.initials: MS
authors.lastname: Zeng
authors.forename: Jian-ye
authors.initials: JY
authors.lastname: Zang
authors.forename: Qiang
authors.initials: Q
authors.lastname: Liu
authors.forename: Feng-xi
authors.initials: FX
authors.lastname: Su
authors.forename: Peter
authors.initials: P
authors.lastname: Zhang
authors.forename: Judy
authors.initials: J
authors.lastname: Lieberman
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.forename: Erwei
authors.initials: E
authors.lastname: Song
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D001943:Breast Neoplasms / Q000378:metabolism* / Q000628:therapy*; D018797:Cell Cycle Proteins / Q000235:genetics*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005260:Female; D006801:Humans; D051379:Mice; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D034741:RNA, Small Interfering / Q000235:genetics / Q000502:physiology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D057127:Single-Chain Antibodies / Q000008:administration & dosage / Q000235:genetics; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays; D000097869:Polo-Like Kinase 1
chemical_list: D018797:Cell Cycle Proteins; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D018719:Erb-b2 Receptor Tyrosine Kinases; D057127:Single-Chain Antibodies; D000097869:Polo-Like Kinase 1