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.
References: Cupaioli FA, Zucca FA, Boraschi D, Zecca L. Engineered nanoparticles. How brain friendly is this new guest? Prog Neurobiol. 2014 Aug-Sep;119-120:20-38. doi: 10.1016/j.pneurobio.2014.05.002. Epub 2014 May 10. Review. PubMed PMID: 24820405.
Frosina G. Nanoparticle-mediated drug delivery to high-grade gliomas. Nanomedicine. 2016 May;12(4):1083-93. doi: 10.1016/j.nano.2015.12.375. Epub 2016 Jan 6. Review. PubMed PMID: 26767516.
Gulyaev AE, Gelperina SE, Skidan IN, Antropov AS, Kivman GY, Kreuter J. Significant transport of doxorubicin into the brain with polysorbate 80-coated nanoparticles. Pharm Res. 1999 Oct;16(10):1564-9. PubMed PMID: 10554098.
Karim R, Palazzo C, Evrard B, Piel G. Nanocarriers for the treatment of glioblastoma multiforme: Current state-of-the-art. J Control Release. 2016 Apr10;227:23-37. doi: 10.1016/j.jconrel.2016.02.026. Epub 2016 Feb 16. Review.PubMed PMID: 26892752.
MacDiarmid JA, Brahmbhatt H. Minicells: versatile vectors for targeted drug or si/shRNA cancer therapy. Curr Opin Biotechnol. 2011 Dec;22(6):909-16. doi: 10.1016/j.copbio.2011.04.008. Epub 2011 May 6. Review. PubMed PMID: 21550793.
MacDiarmid JA, Madrid-Weiss J, Amaro-Mugridge NB, Phillips L, Brahmbhatt H. Bacterially-derived nanocells for tumor-targeted delivery of chemotherapeutics and cell cycle inhibitors. Cell Cycle. 2007 Sep 1;6(17):2099-105. Epub 2007 Jun 27. PubMed PMID: 17786046.
Meng J, Agrahari V, Youm I. Advances in Targeted Drug Delivery Approaches for the Central Nervous System Tumors: The Inspiration of Nanobiotechnology. J Neuroimmune Pharmacol. 2017 Mar;12(1):84-98. doi: 10.1007/s11481-016-9698-1. Epub2016 Jul 23. Review. PubMed PMID: 27449494.
Messaoudi K, Clavreul A, Lagarce F. Toward an effective strategy in glioblastoma treatment. Part I: resistance mechanisms and strategies to overcome resistance of glioblastoma to temozolomide. Drug Discov Today. 2015 Jul;20(7):899-905. doi: 10.1016/j.drudis.2015.02.011. Epub 2015 Mar 2. Review.PubMed PMID: 25744176.
Oberoi RK, Parrish KE, Sio TT, Mittapalli RK, Elmquist WF, Sarkaria JN. Strategies to improve delivery of anticancer drugs across the blood-brain barrier to treat glioblastoma. Neuro Oncol. 2016 Jan;18(1):27-36. doi: 10.1093/neuonc/nov164. Epub 2015 Sep 10. Review. PubMed PMID: 26359209; PubMed Central PMCID: PMC4677418.
Patel TR. Nanocarrier-based therapies for CNS tumors. CNS Oncol. 2014 Mar;3(2):115-22. doi: 10.2217/cns.14.2. Review. PubMed PMID: 25055017.
Peluffo H, Unzueta U, Negro-Demontel ML, Xu Z, Váquez E, Ferrer-Miralles N, Villaverde A. BBB-targeting, protein-based nanomedicines for drug and nucleic acid delivery to the CNS. Biotechnol Adv. 2015 Mar-Apr;33(2):277-87. doi: 10.1016/j.biotechadv.2015.02.004. Epub 2015 Feb 16. Review. PubMed PMID: 25698504.