Spherical nucleic acid nanoparticle conjugates as an RNAi-based therapy for glioblastoma

Samuel A. Jensen, Emily S. Day, Caroline H. Ko, Lisa A. Hurley, Janina P. Luciano, Fotini M. Kouri, Timothy J. Merkel, Andrea C. Luthi, Pinal C. Patel, Joshua I. Cutler, Weston L. Daniel, Alexander W. Scott, Matthew W. Rotz, Thomas J. Meade, David A. Giljohann, Chad A. Mirkin*, Alexander H. Stegh

*Corresponding author for this work

Research output: Contribution to journalArticle

264 Citations (Scopus)

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.

Original languageEnglish (US)
Article number209ra152
JournalScience translational medicine
Volume5
Issue number209
DOIs
StatePublished - Oct 30 2013

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Glioblastoma
RNA Interference
Nanoparticles
Nucleic Acids
Oncogenes
Effector Caspases
Glioma
Therapeutics
Apoptosis
Nanomedicine
Caspase Inhibitors
Oncogene Proteins
Astrocytoma
Cell- and Tissue-Based Therapy
Genomics
Tumor Burden
Blood-Brain Barrier
Neuroglia
Gold
Small Interfering RNA

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Jensen, Samuel A. ; Day, Emily S. ; Ko, Caroline H. ; Hurley, Lisa A. ; Luciano, Janina P. ; Kouri, Fotini M. ; Merkel, Timothy J. ; Luthi, Andrea C. ; Patel, Pinal C. ; Cutler, Joshua I. ; Daniel, Weston L. ; Scott, Alexander W. ; Rotz, Matthew W. ; Meade, Thomas J. ; Giljohann, David A. ; Mirkin, Chad A. ; Stegh, Alexander H. / Spherical nucleic acid nanoparticle conjugates as an RNAi-based therapy for glioblastoma. In: Science translational medicine. 2013 ; Vol. 5, No. 209.
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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.",
author = "Jensen, {Samuel A.} and Day, {Emily S.} and Ko, {Caroline H.} and Hurley, {Lisa A.} and Luciano, {Janina P.} and Kouri, {Fotini M.} and Merkel, {Timothy J.} and Luthi, {Andrea C.} and Patel, {Pinal C.} and Cutler, {Joshua I.} and Daniel, {Weston L.} and Scott, {Alexander W.} and Rotz, {Matthew W.} and Meade, {Thomas J.} and Giljohann, {David A.} and Mirkin, {Chad A.} and Stegh, {Alexander H.}",
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Jensen, SA, Day, ES, Ko, CH, Hurley, LA, Luciano, JP, Kouri, FM, Merkel, TJ, Luthi, AC, Patel, PC, Cutler, JI, Daniel, WL, Scott, AW, Rotz, MW, Meade, TJ, Giljohann, DA, Mirkin, CA & Stegh, AH 2013, 'Spherical nucleic acid nanoparticle conjugates as an RNAi-based therapy for glioblastoma', Science translational medicine, vol. 5, no. 209, 209ra152. https://doi.org/10.1126/scitranslmed.3006839

Spherical nucleic acid nanoparticle conjugates as an RNAi-based therapy for glioblastoma. / Jensen, Samuel A.; Day, Emily S.; Ko, Caroline H.; Hurley, Lisa A.; Luciano, Janina P.; Kouri, Fotini M.; Merkel, Timothy J.; Luthi, Andrea C.; Patel, Pinal C.; Cutler, Joshua I.; Daniel, Weston L.; Scott, Alexander W.; Rotz, Matthew W.; Meade, Thomas J.; Giljohann, David A.; Mirkin, Chad A.; Stegh, Alexander H.

In: Science translational medicine, Vol. 5, No. 209, 209ra152, 30.10.2013.

Research output: Contribution to journalArticle

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T1 - Spherical nucleic acid nanoparticle conjugates as an RNAi-based therapy for glioblastoma

AU - Jensen, Samuel A.

AU - Day, Emily S.

AU - Ko, Caroline H.

AU - Hurley, Lisa A.

AU - Luciano, Janina P.

AU - Kouri, Fotini M.

AU - Merkel, Timothy J.

AU - Luthi, Andrea C.

AU - Patel, Pinal C.

AU - Cutler, Joshua I.

AU - Daniel, Weston L.

AU - Scott, Alexander W.

AU - Rotz, Matthew W.

AU - Meade, Thomas J.

AU - Giljohann, David A.

AU - Mirkin, Chad A.

AU - Stegh, Alexander H.

PY - 2013/10/30

Y1 - 2013/10/30

N2 - 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.

AB - 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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