title: Targeted delivery of CXCR4-siRNA by scFv for HER2(+) breast cancer therapy.
abstract: Therapeutics based on short interfering RNAs (siRNAs) have great potential to treat human diseases. However, the clinical application of siRNAs has been limited by their poor intracellular uptake, low serum stability, and inability to target specific cells. In this study, we addressed this lack of specificity by synthesizing a molecularly targeted CXCR4-siRNA (CXCR4si) for the treatment of HER2(+) breast cancers using a HER2-scFv-arginine nonamer peptide fusion protein (e23sFv-9R) as an siRNA carrier. The e23sFv-9R binding siRNA is able to specifically deliver the siRNA to HER2(+) breast cancer cells and concentrate and persist in orthotopic HER2(+) breast cancer xenografts for at least 36 h. CXCR4si delivered by e23sFv-9R inhibited CXCR4 gene expression, reduced proliferation and metastasis and induced apoptosis in the HER2(+) breast cancer BT-474 cell line in vitro. Moreover, the systemic delivery of CXCR4si by e23sFv-9R is able to suppress tumor growth, reduce metastasis and prolong survival in mice bearing HER2(+) xenografts. This approach causes no systemic toxicity and does not activate the innate immune response, suggesting that a fusion protein carrying CXCR4si shows promise in the treatment of HER2-overexpressing breast cancer.
authors.affiliation: Department of Orthopedics, Tangdu Hospital, Fourth Military Medical University, 569 Xinsi Road, Xi'an 710038, China.
authors.forename: Kuo
authors.initials: K
authors.lastname: Jiang
authors.affiliation: Department of Gynecology and Obstetrics, Xijing Hospital, Fourth Military Medical University, 127 Changle West Road, Xi'an 710032, China.
authors.forename: Jia
authors.initials: J
authors.lastname: Li
authors.affiliation: State Key Laboratory of Cancer Biology, Department of Xijing Hospital of Digestive Diseases, Fourth Military Medical University, 127 Changle West Road, Xi'an 710032, China.
authors.forename: Jipeng
authors.initials: J
authors.lastname: Yin
authors.affiliation: Department of Orthopedics, Tangdu Hospital, Fourth Military Medical University, 569 Xinsi Road, Xi'an 710038, China.
authors.forename: Qiong
authors.initials: Q
authors.lastname: Ma
authors.affiliation: The State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, 169 Changle West Road, Xi'an 710032, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Yan
authors.affiliation: The State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, 169 Changle West Road, Xi'an 710032, China.
authors.forename: Xiang
authors.initials: X
authors.lastname: Zhang
authors.affiliation: The State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, 169 Changle West Road, Xi'an 710032, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Wang
authors.affiliation: The State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, 169 Changle West Road, Xi'an 710032, China.
authors.forename: Lifeng
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Orthopedics, Tangdu Hospital, Fourth Military Medical University, 569 Xinsi Road, Xi'an 710038, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Liu
authors.affiliation: Department of Orthopedics, Tangdu Hospital, Fourth Military Medical University, 569 Xinsi Road, Xi'an 710038, China.
authors.forename: Yinglong
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Orthopedics, Tangdu Hospital, Fourth Military Medical University, 569 Xinsi Road, Xi'an 710038, China.
authors.forename: Qingyu
authors.initials: Q
authors.lastname: Fan
authors.affiliation: The State Key Laboratory of Cancer Biology, Department of Immunology, Fourth Military Medical University, 169 Changle West Road, Xi'an 710032, China. Electronic address: agyang@fmmu.edu.cn.
authors.forename: Angang
authors.initials: A
authors.lastname: Yang
authors.affiliation: Department of Orthopedics, Tangdu Hospital, Fourth Military Medical University, 569 Xinsi Road, Xi'an 710038, China. Electronic address: qiuxiuchun2009@live.cn.
authors.forename: Xiuchun
authors.initials: X
authors.lastname: Qiu
authors.affiliation: Department of Orthopedics, Tangdu Hospital, Fourth Military Medical University, 569 Xinsi Road, Xi'an 710038, China. Electronic address: gukemba@fmmu.edu.cn.
authors.forename: Baoan
authors.initials: B
authors.lastname: Ma
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D018734:Genes, erbB-2; D006801:Humans; D051379:Mice; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000235:genetics; D019718:Receptors, CXCR4 / Q000235:genetics*; D057127:Single-Chain Antibodies / Q000008:administration & dosage*; D023041:Xenograft Model Antitumor Assays
chemical_list: C527276:CXCR4 protein, human; D034741:RNA, Small Interfering; D019718:Receptors, CXCR4; D057127:Single-Chain Antibodies
keywords: Breast cancer therapy; CXCR4; Single-chain antibody fragment; siRNA delivery