ET-61 * NOVEL LIPID NANOPARTICLES FOR THE DELIVERY OF NUCLEIC ACIDS TO GLIOBLASTOMA

Abstract

Glioblastoma (GBM) remains one of the most lethal types of cancer. Novel therapies are urgently needed for patients with GBM. Recently we demonstrated high expression of ZEB-1 but low expression of microRNA-200 (miR-200) in GBM samples, and that suppressing ZEB-1 expression or re-expressing miR-200 in GBM cells decreased GBM invasion, increased sensitivity to the chemotherapy temozolomide, and prolonged survival in mouse xenotransplantation studies. Therefore, using nucleic acids to modify ZEB-1 or miR-200 expression is a potential novel GBM therapeutic strategy. However, the transport technology that enables nucleic acids to cross the blood brain barrier (BBB) and enter GBM is not available. Brain microvascular endothelial cells (BMEC) found in the BBB are lined with caveolin, scavenger receptors class B type I (SR-B1), and low-density lipoprotein receptors (LDLr), which are essential to the endocytosis/ transcytosis processes of BMEC. We engineered a novel lipid nanoparticle (LNP) that targets caveolin, SR-BI, and LDLr on BMEC. The LNP is composed of phosphatidylcholine (PC), cholesterol (Chol) and poloxamer (PXR). Flow cytometric analysis indicates that LNP composed of PC/Chol/PXR are avidly taken up by BMEC, approximately 23-fold higher than LNP composed of PC only. Intravenous injection of PC/Chol/PXR, but not PC, LNP in mice leads to their accumulation in the central nervous system including the hippocampus and the cerebellum. Fluorescent microscopy reveals that PC/Chol/PXR LNP efficiently delivers fluorescent nucleic acids to human GBM cells, which express 2- to 5-fold higher levels of caveolin than normal brain cells. Our data indicate that the innovative PC/Chol/PXR LNP has high potential to deliver nucleic acids to GBM in vivo, and enable the utility of nucleic acids as a therapeutic modality against GBM. (Supported by UF Research Opportunity Seed Fund, McKnight Brain Institute Therapeutic Discovery and Translational Research Award, NIH/NINDS NS055165 and the McKinney, Maren, and Thompson Regenerative Medicine Funds).