title: Spherical nucleic acid nanoparticle conjugates as an RNAi-based therapy for glioblastoma.
abstract: Glioblastoma multiforme (GBM) is a neurologically debilitating disease that culminates in death 14 to 16 months after diagnosis. An incomplete understanding of how cataloged genetic aberrations promote therapy resistance, combined with ineffective drug delivery to the central nervous system, has rendered GBM incurable. Functional genomics efforts have implicated several oncogenes in GBM pathogenesis but have rarely led to the implementation of targeted therapies. This is partly because many "undruggable" oncogenes cannot be targeted by small molecules or antibodies. We preclinically evaluate an RNA interference (RNAi)-based nanomedicine platform, based on spherical nucleic acid (SNA) nanoparticle conjugates, to neutralize oncogene expression in GBM. SNAs consist of gold nanoparticles covalently functionalized with densely packed, highly oriented small interfering RNA duplexes. In the absence of auxiliary transfection strategies or chemical modifications, SNAs efficiently entered primary and transformed glial cells in vitro. In vivo, the SNAs penetrated the blood-brain barrier and blood-tumor barrier to disseminate throughout xenogeneic glioma explants. SNAs targeting the oncoprotein Bcl2Like12 (Bcl2L12)--an effector caspase and p53 inhibitor overexpressed in GBM relative to normal brain and low-grade astrocytomas--were effective in knocking down endogenous Bcl2L12 mRNA and protein levels, and sensitized glioma cells toward therapy-induced apoptosis by enhancing effector caspase and p53 activity. Further, systemically delivered SNAs reduced Bcl2L12 expression in intracerebral GBM, increased intratumoral apoptosis, and reduced tumor burden and progression in xenografted mice, without adverse side effects. Thus, silencing antiapoptotic signaling using SNAs represents a new approach for systemic RNAi therapy for GBM and possibly other lethal malignancies.
authors.affiliation: Ken and Ruth Davee Department of Neurology, The Northwestern Brain Tumor Institute, The Robert H. Lurie Comprehensive Cancer Center, Northwestern University, 303 East Superior, Chicago, IL 60611, USA.
authors.forename: Samuel A
authors.initials: SA
authors.lastname: Jensen
authors.forename: Emily S
authors.initials: ES
authors.lastname: Day
authors.forename: Caroline H
authors.initials: CH
authors.lastname: Ko
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Hurley
authors.forename: Janina P
authors.initials: JP
authors.lastname: Luciano
authors.forename: Fotini M
authors.initials: FM
authors.lastname: Kouri
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Merkel
authors.forename: Andrea J
authors.initials: AJ
authors.lastname: Luthi
authors.forename: Pinal C
authors.initials: PC
authors.lastname: Patel
authors.forename: Joshua I
authors.initials: JI
authors.lastname: Cutler
authors.forename: Weston L
authors.initials: WL
authors.lastname: Daniel
authors.forename: Alexander W
authors.initials: AW
authors.lastname: Scott
authors.forename: Matthew W
authors.initials: MW
authors.lastname: Rotz
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Meade
authors.forename: David A
authors.initials: DA
authors.lastname: Giljohann
authors.forename: Chad A
authors.initials: CA
authors.lastname: Mirkin
authors.forename: Alexander H
authors.initials: AH
authors.lastname: Stegh
mesh_terms: D000818:Animals; D017209:Apoptosis; D001812:Blood-Brain Barrier / Q000378:metabolism / Q000473:pathology; D001932:Brain Neoplasms / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D045744:Cell Line, Tumor; D015536:Down-Regulation; D005260:Female; D005909:Glioblastoma / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D009124:Muscle Proteins / Q000378:metabolism; D053758:Nanoparticles / Q000737:chemistry*; D009696:Nucleic Acids / Q000008:administration & dosage / Q000737:chemistry*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D034622:RNA Interference; D047368:Tumor Burden; D023041:Xenograft Model Antitumor Assays
chemical_list: C430100:BCL2L12 protein, human; D009124:Muscle Proteins; D009696:Nucleic Acids; D019253:Proto-Oncogene Proteins c-bcl-2