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  • Paramagnetic Nanoparticles Conjugated with Lipopolysaccharide for Blood-Brain Barrier Disruption in a Murine Model of Glioblastoma

    Final Number:

    Andrew Joshua Kobets MD, MHS; Muhammad Babar Khan MD; Mahantesh Navati PhD; Kevin Kwan MD; Yao Liu MD; Jonathan P Nakhla MD; Joel Friedman MD, PhD; John A. Boockvar MD; Rosamaria Ruggieri PhD; Marc H. Symons PhD

    Study Design:
    Laboratory Investigation

    Subject Category:

    Meeting: Congress of Neurological Surgeons 2018 Annual Meeting

    Introduction: Glioblastoma (GBM) is the most aggressive primary adult brain tumor with only 14.6 months 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. Afterwards, 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=.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=.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).

    Conclusions: The BBB can be safely and reversibly disrupted for targeted permeability of large molecules in a GBM model. 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.

    Patient Care: This research may open additional avenues for therapeutic delivery which may not have been considered by other researchers. This work establishes a groundwork for blood brain barrier disruption and therapeutic delivery in the future in this model of glioblastoma. If safe and effective, the use of these particles packaged with therapeutics may be trialed in humans in the future.

    Learning Objectives: By the conclusion of this session, participants should be able to: 1) Describe the importance of blood brain barrier breakdown for the delivery of therapeutics in glioblastoma, 2) Discuss, in small groups, strategies for therapeutic penetration in glioblastoma and determine mechanisms for LPS effects on tumor and endothelial cells, 3) Identify an effective treatment for blood brain barrier impermeability and strategize possible glioblastoma treatments in the future.

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