Glioblastoma (GBM) is a notoriously difficult cancer to treat due to the fact that there are limited targeted therapies available that can successfully cross the blood-brain barrier. Spherical nucleic acids (SNAs) offer a potential solution to this problem. SNAs consist of a gold nanoparticle core with covalently conjugated small interfering RNA (siRNA) which is arranged in a radial orientation. The SNA known as NU-0129 has previously demonstrated GBM tumour penetration, crossing the blood-brain barrier, in an animal model. Suppressing the expression of the GBM oncogene Bcl2L12, treatment with these SNAs resulted in a 3 to 4-fold decrease in tumour size and a 20% increase in overall survival(1).
In light of these results, the pharmacokinetics, intratumour accumulation and gene-suppression activity of NU-0129 has recently been evaluated in a phase 0 trial in 8 patients with recurrent GBM. Administered intravenously, patients received a dose 1/50th of the no-observed-adverse-event level, followed by tumour resection. Inductively coupled plasma mass spectrometry, x-ray fluorescence microscopy and silver staining of resected GBM tumour tissue clearly showed NU-0129 tumour infiltration, with gold enrichment observed in tumour-associated endothelium, macrophages and tumour cells. Furthermore, the uptake of NU-0129 into glioma cells was clearly correlated with a reduction in tumour-associated Bcl2L12 protein expression, when matched primary tumour samples were compared to NU-0129-trated recurrent tumour samples. Importantly, no grade 4 or 5 treatment-related adverse events were reported.(2)
This first-in-human trial clearly demonstrated preliminary efficacy with the SNA NU-0129. Although promising, this data needs to validated in a larger cohort study, complete with primary survival outcomes.