HDL Nanodiscs Loaded with Liver X Receptor Agonist Decreases Tumor Burden and Mediates Long-term Survival in Mouse Glioma Model.

Abstract

Glioblastoma multiforme (GBM) is a highly aggressive primary brain tumor with a 5-year survival rate of 7%. Previous studies have shown that GBM tumors have a reduced capacity to produce cholesterol and instead depend on the uptake of cholesterol produced by astrocytes. To target cholesterol metabolism to induce cancer cell death, synthetic high-density lipoprotein (sHDL) nanodiscs delivering Liver-X-Receptor (LXR) agonists and CpG oligonucleotides for targeting GBM are investigated. LXR agonists synergize with sHDL nanodiscs by increasing the expression of the ABCA1 cholesterol efflux transporter, resulting in further depletion of cholesterol reserves within tumors, and CpG oligonucleotides are established adjuvants used in cancer immunotherapy that work through the toll-like receptor 9 pathway. In the present study, treatment with GW-CpG-sHDL nanodiscs increases the expression of cholesterol efflux transporters on murine GL261 cells leading to enhanced cholesterol removal. Experiments in GL261-tumor-bearing mice reveal combining GW-CpG-sHDL nanodiscs with radiation (IR) therapy significantly increases median survival compared to GW-CpG-sHDL or IR alone. Furthermore, 66% of long-term survivors from the GW-CpG-sHDL +IR treatment group show no tumor tissue when rechallenged.