title: RNA Nanoparticle-Based Targeted Therapy for Glioblastoma through Inhibition of Oncogenic miR-21.
abstract: Targeted inhibition of oncogenic miRNA-21 has been proposed to treat glioblastoma by rescuing tumor suppressors, PTEN and PDCD4. However, systemic delivery of anti-miR-21 sequences requires a robust and efficient delivery platform to successfully inhibit this druggable target. Three-way-junction (3WJ)-based RNA nanoparticles (RNP), artificially derived from pRNA of bacteriophage phi29 DNA packaging motor, was recently shown to target glioblastoma. Here, we report that multi-valent folate (FA)-conjugated 3WJ RNP constructed to harbor anti-miR-21 LNA sequences (FA-3WJ-LNA-miR21) specifically targeted and delivered anti-miR-21 LNA and knocked down miR-21 expression in glioblastoma cells in vitro and in vivo with favorable biodistribution. Systemically injected FA-3WJ-LNA-miR21 RNP efficiently rescued PTEN and PDCD4, resulting in glioblastoma cell apoptosis and tumor growth regression. Overall survival rate was also significantly improved by FA-3WJ-LNA-miR21 RNP. These results are indicative of the clinical benefit of FA-3WJ RNP-based gene therapy for the successful targeted therapy of developing and even recurring glioblastoma.
authors.affiliation: Department of Cancer Biology and Genetics, College of Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA.
authors.forename: Tae Jin
authors.initials: TJ
authors.lastname: Lee
authors.affiliation: Department of Neurological Surgery, College of Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA.
authors.forename: Ji Young
authors.initials: JY
authors.lastname: Yoo
authors.affiliation: Division of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA; Department of Physiology and Cell Biology, Dorothy M. Davis Heart and Lung Research Institute, College of Medicine, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Dan
authors.initials: D
authors.lastname: Shu
authors.affiliation: Division of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA; Department of Physiology and Cell Biology, Dorothy M. Davis Heart and Lung Research Institute, College of Medicine, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Biomedical Informatics, Center for Biostatistics, Comprehensive Cancer Center, The Ohio State University Medical Center, Columbus, OH 43210, USA.
authors.forename: Jianying
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Otolaryngology, Head & Neck Surgery, The Ohio State University Medical Center, Columbus, OH 43210, USA.
authors.forename: Jun-Ge
authors.initials: JG
authors.lastname: Yu
authors.affiliation: Department of Neurological Surgery, College of Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA.
authors.forename: Alena Cristina
authors.initials: AC
authors.lastname: Jaime-Ramirez
authors.affiliation: Department of Cancer Biology and Genetics, College of Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA.
authors.forename: Mario
authors.initials: M
authors.lastname: Acunzo
authors.affiliation: Department of Cancer Biology and Genetics, College of Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA.
authors.forename: Giulia
authors.initials: G
authors.lastname: Romano
authors.affiliation: Department of Cancer Biology and Genetics, College of Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA.
authors.forename: Ri
authors.initials: R
authors.lastname: Cui
authors.affiliation: Department of Cancer Biology and Genetics, College of Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA.
authors.forename: Hui-Lung
authors.initials: HL
authors.lastname: Sun
authors.affiliation: Department of Cancer Biology and Genetics, College of Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA.
authors.forename: Zhenghua
authors.initials: Z
authors.lastname: Luo
authors.affiliation: Department of Otolaryngology, Head & Neck Surgery, The Ohio State University Medical Center, Columbus, OH 43210, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Old
authors.affiliation: Department of Neurological Surgery, College of Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA.
authors.forename: Balveen
authors.initials: B
authors.lastname: Kaur
authors.affiliation: Division of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA; Department of Physiology and Cell Biology, Dorothy M. Davis Heart and Lung Research Institute, College of Medicine, The Ohio State University, Columbus, OH 43210, USA. Electronic address: guo.1091@osu.edu.
authors.forename: Peixuan
authors.initials: P
authors.lastname: Guo
authors.affiliation: Department of Cancer Biology and Genetics, College of Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA. Electronic address: carlo.croce@osumc.edu.
authors.forename: Carlo M
authors.initials: CM
authors.lastname: Croce
mesh_terms: D000818:Animals; D000070416:Antagomirs / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D001932:Brain Neoplasms / Q000235:genetics / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D045744:Cell Line, Tumor; D004337:Drug Carriers; D005260:Female; D058973:Folate Receptors, GPI-Anchored / Q000235:genetics / Q000378:metabolism; D005492:Folic Acid / Q000737:chemistry / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000235:genetics / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry; D009841:Oligonucleotides / Q000737:chemistry / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D016019:Survival Analysis; D023041:Xenograft Model Antitumor Assays
chemical_list: D000070416:Antagomirs; D051017:Apoptosis Regulatory Proteins; D004337:Drug Carriers; D058973:Folate Receptors, GPI-Anchored; C524940:MIRN21 microRNA, human; D035683:MicroRNAs; D009841:Oligonucleotides; C114487:PDCD4 protein, human; D016601:RNA-Binding Proteins; C477371:locked nucleic acid; D005492:Folic Acid; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human
keywords: 3WJ; RNA nanoparticle; apoptosis; glioblastoma; microRNA