Andrew J Kobets
Children's Hospital, USA
Title: Paramagnetic nanoparticles conjugated with lipopolysaccharide for blood-brain barrier disruption in a model of glioblastoma
Biography
Biography: Andrew J Kobets
Abstract
Background: Glioblastoma (GBM) is the most aggressive primary adult brain tumor with only 14.6 months of median survival. Carrier nanoparticles have emerged as a novel strategy for chemotherapeutic delivery, yet penetration of the blood-brain barrier (BBB) and tumor retention remain significant hurdles. The evolution of paramagnetic nanoparticles (PMNPs) shows promise for reliable, magnetically-targeted drug delivery, and coupled with a lipopolysaccharide-coating (LPS-PMNPs) allows for concurrent, reversible BBB disruption.
Methods: Luciferase-expressing GBM6 cells were implanted intracranially in nu/nu immunodeficient mice to model GBM in two experiments. First, bioluminescence assays (BLIs) characterized tumor growth postoperatively in cohorts administered LPS-PMNPs, inert PNMPs (OA-PMNP), or saline intravenously at four weeks. Magnets were positioned external to the tumor for one-hour post-injection. Subsequent BLIs trended tumor growth with survival. The second experiment involved LPS-PMNPs, OA-PMNPs, or saline injection postoperatively, followed by magnetic localization. Afterward, Evans blue dye (EBD) was administered as an albumin-bound marker of BBB breakdown. The mice were perfused, the tumors homogenized, and the dye extracted for spectrophotometric assessment.
Results: Tumor size doubled every 5.8 days, and mice expired at a mean 52 days. LPS-PMNPs reduced BLI signal three days post-injection compared to both OA-PMNPs and saline (p=0.02). This effect was reversed six days post-injection (p=0.39). EBD was significantly extravasated in LPS-PMNP-treated tumors compared to all other tumors (p=0.011). No immediate particle-associated adverse reactions occurred and survival was similar between all groups (p=0.27) with a trend toward survival between the LPS group and highest-dose PMNP group (53.5 vs. 47.8 days, p=0.12).
Conclusion: The BBB can be safely and reversibly disrupted for targeted permeability of large molecules in a model of GBM. LPS induces transient disruption of bioluminescence of tumors and increases tumor absorption of albumin-bound EBD. Future work will start with packaging known chemotherapeutics not normally BBB permeable in LPS-PMNPs to determine delivery efficacy and anti-neoplastic effects on survival.