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Cited by 592RNA Interference and Gene DeliveryNanoparticle-Based Drug DeliveryGlioma Diagnosis and Treatment

Spherical Nucleic Acid Nanoparticle Conjugates as an RNAi-Based Therapy for Glioblastoma

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Jensen, Samuel A., Day, Emily S., Ko, Caroline H., Hurley, Lisa A., Luciano, Janina P., Kouri, Fotini M., Merkel, Timothy J., Luthi, Andrea J. +9 more·2013·Science Translational Medicine
DOI 10.1126/scitranslmed.3006839PMC PMC4017940
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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.

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  • To cross tissue barriers, nanoparticles are either negatively charged on the surface, or capable of binding to receptors on the cell surface, or densely packed around a metal core.

    “To cross the tissue barriers, nanoparticles are either negatively charged on the surface (519), or capable of binding to receptors on the cell surface (670), or densely packed around a metal core (291).”

    From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [291]

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Authors
Jensen, S. A., Day, E. S., Ko, C. H., Hurley, L. A., Luciano, J. P., Kouri, F. M., Merkel, T. J., Luthi, A. J., Patel, P. C., Cutler, J. I., Daniel, W. L., Scott, A. W., Rotz, M. W., Meade, T. J., Giljohann, D. A., Mirkin, C. A., & Stegh, A. H.
Affiliations
Northwestern University (US)
Corresponding author
  • Jensen, Samuel A.
  • Day, Emily S.
  • Ko, Caroline H.
  • Mirkin, Chad A.
  • Stegh, Alexander H.
ORCID
Venue
Science Translational Medicine
Publisher
American Association for the Advancement of Science (AAAS)
Published
2013-10-30
Volume
5
Issue
209
Pages
209ra152-209ra152
ISSN
  • 1946-6234 (ISSN-L)
  • 1946-6242
DOI
10.1126/scitranslmed.3006839
PMC
PMC4017940
OpenAlex
W2121322725
Cited by
592
References
2
Citations by year
2026: 29 · 2025: 37 · 2024: 46 · 2023: 45 · 2022: 52 · 2021: 52 · 2020: 45 · 2019: 52 · 2018: 55 · 2017: 46 · 2016: 48 · 2015: 51 · 2014: 28 · 2013: 5 · 2012: 1
FWCI
19.72
Type
journal article
Language
en
Open access
Locations
  • Science Translational Medicine (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Cancer Institute (F32CA171949, T32 CA09560, U54CA151880, P30CA060553, T32CA009560)
  • National Institute of Arthritis and Musculoskeletal and Skin Diseases (R21AR062898, P30AR057216, R01AR060810)
  • National Institute of Biomedical Imaging and Bioengineering (R01EB005866)
  • National Center for Research Resources (S10RR023707)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
  • Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
  • Health Sciences › Medicine › Genetics › Glioma Diagnosis and Treatment
Keywords
glioblastoma, spherical nucleic acids, RNA interference, gold nanoparticles, BCL2L12, p53, caspase activation, apoptosis, blood-brain barrier, blood-tumor barrier, nanomedicine, oncogene silencing, xenograft tumor model
MeSH terms
Animals, Blood-Brain Barrier, Brain Neoplasms, Female, Glioblastoma, Humans, Muscle Proteins, Nucleic Acids, Down-Regulation, Mice, SCID, Apoptosis, Proto-Oncogene Proteins c-bcl-2, Xenograft Model Antitumor Assays, RNA Interference, Cell Line, Tumor, Tumor Burden, Mice, Nanoparticles

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