title: Brain tumor-targeted therapy by systemic delivery of siRNA with Transferrin receptor-mediated core-shell nanoparticles.
abstract: Treatment of brain tumor remains a great challenge worldwide. Development of a stable, safe, and effective siRNA delivery system which is able to cross the impermeable blood-brain barrier (BBB) and target glioma cells is necessary. This study aims to investigate the therapeutic effects of intravenous administration of T7 peptide modified core-shell nanoparticles (named T7-LPC/siRNA NPs) on brain tumors. Layer-by-layer assembling of protamine/chondroitin sulfate/siRNA/cationic liposomes followed by T7 peptide modification has been carried out in order to obtain a targeted siRNA delivery system. In vitro cellular uptake experiments demonstrated a higher intracellular fluorescence intensity of siRNA in brain microvascular endothelial cells (BMVECs) and U87 glioma cells when treated with T7-LPC/siRNA NPs compared with PEG-LPC/siRNA NPs. In the co-culture model of BMVECs and U87 cells, a significant down-regulation of EGFR protein expression occurred in the U87 glioma cells after treatment with the T7-LPC/siEGFR NPs. Moreover, the T7-LPC/siRNA NPs had an advantage in penetrating into a deep region of the tumor spheroid compared with PEG-LPC/siRNA NPs. In vivo imaging revealed that T7-LPC/siRNA NPs accumulated more specifically in brain tumor tissues than the non-targeted NPs. Also, in vivo tumor therapy experiments demonstrated that the longest survival period along with the greatest downregulation of EGFR expression in tumor tissues was observed in mice with an intracranial U87 glioma treated with T7-LPC/siEGFR NPs compared with mice receiving other formulations. Therefore, we believe that these transferrin receptor-mediated core-shell nanoparticles are an important potential siRNA delivery system for brain tumor-targeted therapy.
authors.affiliation: Department of Pharmaceutics, College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, China; Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 38 Xueyuan Road, 100191, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Wei
authors.affiliation: Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 38 Xueyuan Road, 100191, China.
authors.forename: Xi-Ying
authors.initials: XY
authors.lastname: Guo
authors.affiliation: Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 38 Xueyuan Road, 100191, China.
authors.forename: Ting
authors.initials: T
authors.lastname: Yang
authors.affiliation: Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 38 Xueyuan Road, 100191, China.
authors.forename: Min-Zhi
authors.initials: MZ
authors.lastname: Yu
authors.affiliation: Department of Pharmaceutics, College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, China. Electronic address: chendawei@syphu.edu.cn.
authors.forename: Da-Wei
authors.initials: DW
authors.lastname: Chen
authors.affiliation: Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 38 Xueyuan Road, 100191, China. Electronic address: wang-jc@bjmu.edu.cn.
authors.forename: Jian-Cheng
authors.initials: JC
authors.lastname: Wang
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D018014:Gene Transfer Techniques; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D053758:Nanoparticles / Q000008:administration & dosage* / Q000378:metabolism; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000235:genetics / Q000378:metabolism; D011990:Receptors, Transferrin / Q000008:administration & dosage* / Q000235:genetics / Q000378:metabolism
chemical_list: D034741:RNA, Small Interfering; D011990:Receptors, Transferrin
keywords: Core-shell nanoparticle; Gene therapy; Glioma; Targeted delivery; siRNA