Glioblastoma (GBM) is one of the most difficult
cancers to effectively treat, in part because of the lack of precision
therapies and limited therapeutic access to intracranial
tumor sites due to the presence of the blood-brain and blood-
tumor barriers. We have developed a
precision medicine approach for GBM treatment that involves the use of brain-penetrant RNA interference-based spherical
nucleic acids (SNAs), which consist of
gold nanoparticle cores covalently conjugated with radially oriented and densely packed
small interfering RNA (
siRNA)
oligonucleotides. On the basis of previous preclinical evaluation, we conducted toxicology and toxicokinetic studies in nonhuman primates and a single-arm, open-label phase 0 first-in-human trial (NCT03020017) to determine safety, pharmacokinetics, intratumoral accumulation and gene-suppressive activity of systemically administered SNAs carrying
siRNA specific for the GBM oncogene Bcl2Like12 (Bcl2L12). Patients with recurrent GBM were treated with
intravenous administration of siBcl2L12-SNAs (drug moniker: NU-0129), at a dose corresponding to 1/50th of the no-observed-adverse-event level, followed by
tumor resection. Safety assessment revealed no grade 4 or 5 treatment-related toxicities. Inductively coupled plasma mass spectrometry, x-ray fluorescence microscopy, and
silver staining of resected GBM tissue demonstrated that intravenously administered SNAs reached patient
tumors, with
gold enrichment observed in the
tumor-associated endothelium, macrophages, and
tumor cells. NU-0129 uptake into
glioma cells correlated with a reduction in
tumor-associated Bcl2L12
protein expression, as indicated by comparison of matched primary
tumor and NU-0129-treated recurrent
tumor. Our results establish SNA
nanoconjugates as a potential brain-penetrant
precision medicine approach for the systemic treatment of GBM.