Glioblastoma multiforme is a universally lethal
brain tumor that largely resists current surgical and drug interventions. Despite important advancements in understanding GBM biology, the invasiveness and heterogeneity of these
tumors has made it challenging to develop effective
therapies. Therapeutic
oligonucleotides-antisense oligonucleotides and small-interfering RNAs-are chemically modified
nucleic acids that can silence gene expression in the brain. However, activity of these
oligonucleotides in
brain tumors remains inadequately characterized. In this study, we developed a quantitative method to differentiate
oligonucleotide-induced gene silencing in orthotopic GBM xenografts from gene silencing in normal brain tissue, and used this method to test the differential silencing activity of a chemically diverse panel of
oligonucleotides. We show that
oligonucleotides chemically optimized for pharmacological activity in normal brain tissue do not show consistent activity in GBM xenografts. We then survey multiple advanced
oligonucleotide chemistries for their activity in GBM xenografts. Attaching
lipid conjugates to
oligonucleotides improves silencing in GBM cells across several different
lipid classes. Highly hydrophobic
lipid conjugates
cholesterol and
docosanoic acid enhance silencing but at the cost of higher neurotoxicity. Moderately hydrophobic,
unsaturated fatty acid and amphiphilic
lipid conjugates still improve activity without compromising safety. These
oligonucleotide conjugates show promise for treating
glioblastoma.