title: Anti-Her2 single-chain antibody mediated DNMTs-siRNA delivery for targeted breast cancer therapy.
abstract: The targeted delivery of small interfering RNA (siRNA) to specific tumor tissues and tumor cells remains as one of the key challenges in the development of RNA interference as a therapeutic application. To target breast cancer, we developed a therapeutic delivery system using a fusion protein of an anti-Her2 single-chain antibody fragment with a positively charged protamine, namely F5-P, as the carrier to specifically deliver siRNA-targeting DNA methyltransferases 1 and/or 3b genes (siDNMTs) into Her2-expressing breast tumor cells. The carrier F5-P, expressed by the Escherichia coli system, was able to bind siRNA molecules and specifically deliver the siRNA to Her2-expressing BT474 breast cancer cells but not Her2-nonexpressing MDA-MB-231 breast cancer cells, while delivery of siDNMTs to BT474 cells successfully silenced the expression of targeted DNA methyltransferases (DNMTs) and facilitated the de-methylation of the RASSF1A tumor suppressor gene promoter, leading to the suppression of tumor cell proliferation. Moreover, as demonstrated in the BT474 xenograft murine model, F5-P successfully delivered siRNA into a Her2-expressing breast tumor, and tumor growth inhibition was mediated by an intravenous injection of F5-P/siDNMTs complex by down-regulating the expression of DNMTs and restoring tumor suppressor gene expression. These data suggest that the delivery of siDNMTs by F5-P could be used to treat Her2-expressing breast cancer.
authors: CAS Key Laboratory of Brain Function and Disease, and School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230027, P.R. China.
authors: Shuang
authors: S
authors: Dou
authors: Yan-Dan
authors: YD
authors: Yao
authors: Xian-Zhu
authors: XZ
authors: Yang
authors: Tian-Meng
authors: TM
authors: Sun
authors: Cheng-Qiong
authors: CQ
authors: Mao
authors: Er-Wei
authors: EW
authors: Song
authors: Jun
authors: J
authors: Wang
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000628:therapy*; D045744:Cell Line, Tumor; D015254:DNA Modification Methylases / Q000235:genetics* / Q000378:metabolism; D005260:Female; D020868:Gene Silencing; D006801:Humans; D007128:Immunoglobulin Fragments / Q000008:administration & dosage*; D051379:Mice; D008807:Mice, Inbred BALB C; D011479:Protamines / Q000008:administration & dosage*; D034741:RNA, Small Interfering / Q000008:administration & dosage*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000276:immunology*; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage; D023041:Xenograft Model Antitumor Assays
chemical_list: D015254:DNA Modification Methylases; D007128:Immunoglobulin Fragments; D011479:Protamines; D034741:RNA, Small Interfering; D018719:Erb-b2 Receptor Tyrosine Kinases; D011993:Recombinant Fusion Proteins; C508053:ERBB2 protein, human