Quantifying the activity profile of ASO and siRNA conjugates in glioblastoma xenograft tumors in vivo.

Publisher: Oxford University Press Country of Publication: England NLM ID: 0411011 Publication Model: Print Cited Medium: Internet ISSN: 1362-4962 (Electronic) Linking ISSN: 03051048 NLM ISO Abbreviation: Nucleic Acids Res Subsets: MEDLINE

Publication: 1992- : Oxford : Oxford University Press
Original Publication: London, Information Retrieval ltd.

Glioblastoma*/genetics ; Glioblastoma*/metabolism ; Glioblastoma*/pathology ; RNA, Small Interfering*/genetics ; RNA, Small Interfering*/chemistry ; RNA, Small Interfering*/metabolism ; RNA, Small Interfering*/therapeutic use ; Xenograft Model Antitumor Assays* ; Brain Neoplasms*/genetics ; Oligonucleotides, Antisense*/chemistry ; Oligonucleotides, Antisense*/therapeutic use; Animals ; Humans ; Mice ; Cell Line, Tumor ; Gene Silencing ; Mice, Nude

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.
(© The Author(s) 2024. Published by Oxford University Press on behalf of Nucleic Acids Research.)

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S10 OD020012 United States OD NIH HHS; American Cancer Society; F31 CA261151 United States GF NIH HHS

Date Created: 20240413 Date Completed: 20240522 Latest Revision: 20240612

20240612

PMC11109979

10.1093/nar/gkae260

38613388