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

siRNA-based spherical nucleic acid (SNA) nanoparticle conjugates silence antiapoptosis signaling and impair GBM progression. Nanotechnology Fights Brain Cancer Glioblastoma brain tumors are notoriously difficult to kill because the cancer typically recurs after surgical, chemotherapeutic, and biological assault. Now, Jensen and colleagues describe a new nanoparticle conjugate that can cross the blood-brain barrier (BBB), enter the tumor, and target a known oncogene, thus dismantling the cancer-promoting signals and inducing apoptosis of glioma cells. The nanoparticles, called spherical nucleic acids (SNAs), consisted of densely packed small interfering RNA (siRNA) surrounding a gold core. The siRNA, in this case, targeted the oncogene Bcl2L12 to shut down gene activity in human glioma cell lines and patient-derived tumor neurospheres. When delivered systemically to mice, the SNA nanoparticles rapidly accumulated in the brain—primarily in the tumors—demonstrating their ability to cross the BBB. Animals harboring human brain tumors were then treated with the siRNA-loaded SNAs. Jensen et al. noted impaired tumor growth, likely as the result of increased glioma cell apoptosis, and hence increased survival. This nanomedicine-based strategy could overcome many of the limitations of traditional cancer therapeutics, including inability to cross the BBB and disseminate throughout brain tissue. To move into patients, however, more optimization of the SNA platform will be necessary, as well as additional testing in animal models of human glioblastoma. 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.