title: Minimizing the non-specific binding of nanoparticles to the brain enables active targeting of Fn14-positive glioblastoma cells.
abstract: A major limitation in the treatment of glioblastoma (GBM), the most common and deadly primary brain cancer, is delivery of therapeutics to invading tumor cells outside of the area that is safe for surgical removal. A promising way to target invading GBM cells is via drug-loaded nanoparticles that bind to fibroblast growth factor-inducible 14 (Fn14), thereby potentially improving efficacy and reducing toxicity. However, achieving broad particle distribution and nanoparticle targeting within the brain remains a significant challenge due to the adhesive extracellular matrix (ECM) and clearance mechanisms in the brain. In this work, we developed Fn14 monoclonal antibody-decorated nanoparticles that can efficiently penetrate brain tissue. We show these Fn14-targeted brain tissue penetrating nanoparticles are able to (i) selectively bind to recombinant Fn14 but not brain ECM proteins, (ii) associate with and be internalized by Fn14-positive GBM cells, and (iii) diffuse within brain tissue in a manner similar to non-targeted brain penetrating nanoparticles. In addition, when administered intracranially, Fn14-targeted nanoparticles showed improved tumor cell co-localization in mice bearing human GBM xenografts compared to non-targeted nanoparticles. Minimizing non-specific binding of targeted nanoparticles in the brain may greatly improve the access of particulate delivery systems to remote brain tumor cells and other brain targets.
authors.affiliation: Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, MD 21201, USA; Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
authors.forename: Craig S
authors.initials: CS
authors.lastname: Schneider
authors.affiliation: Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, MD 21201, USA; Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
authors.forename: Jimena G
authors.initials: JG
authors.lastname: Perez
authors.affiliation: Department of Surgery, University of Maryland School of Medicine, Baltimore, MD 21201, USA; Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
authors.forename: Emily
authors.initials: E
authors.lastname: Cheng
authors.affiliation: Center for Nanomedicine, Johns Hopkins University School of Medicine, 400 North Broadway Street, Baltimore, MD 21231, USA.
authors.forename: Clark
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Center for Nanomedicine, Johns Hopkins University School of Medicine, 400 North Broadway Street, Baltimore, MD 21231, USA.
authors.forename: Panagiotis
authors.initials: P
authors.lastname: Mastorakos
authors.affiliation: Center for Nanomedicine, Johns Hopkins University School of Medicine, 400 North Broadway Street, Baltimore, MD 21231, USA.
authors.forename: Justin
authors.initials: J
authors.lastname: Hanes
authors.affiliation: Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD 21201, USA; Department of Surgery, University of Maryland School of Medicine, Baltimore, MD 21201, USA; Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Winkles
authors.affiliation: Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, MD 21201, USA; Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD 21201, USA. Electronic address: gwoodworth@smail.umaryland.edu.
authors.forename: Graeme F
authors.initials: GF
authors.lastname: Woodworth
authors.affiliation: Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, MD 21201, USA; Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD 21201, USA; Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MD 21201, USA. Electronic address: akim@smail.umaryland.edu.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Kim
mesh_terms: D000818:Animals; D000906:Antibodies / Q000378:metabolism; D001692:Biological Transport; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D004622:Embryo, Mammalian / Q000166:cytology; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D005909:Glioblastoma / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007700:Kinetics; D051379:Mice; D053758:Nanoparticles / Q000737:chemistry*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D017207:Rats, Sprague-Dawley; D018124:Receptors, Tumor Necrosis Factor / Q000737:chemistry / Q000378:metabolism*; D020349:Surface Plasmon Resonance; D000074050:TWEAK Receptor; D014018:Tissue Distribution; D023041:Xenograft Model Antitumor Assays
chemical_list: D000906:Antibodies; D016326:Extracellular Matrix Proteins; D018124:Receptors, Tumor Necrosis Factor; C000613297:TNFRSF12A protein, human; D000074050:TWEAK Receptor; C000613299:Tnfrsf12a protein, mouse; C000613300:Tnfrsf12a protein, rat
keywords: Brain tissue penetration; Fibroblast growth factor-inducible 14 (Fn14); Glioblastoma (GBM); Multiple particle tracking (MPT); Surface plasmon resonance (SPR); Targeted nanoparticles