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WIREs Nanomed Nanobiotechnol
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Tumor‐targeted nanotherapeutics: overcoming treatment barriers for glioblastoma

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Glioblastoma (GBM) is a highly aggressive and lethal form of primary brain cancer. Numerous barriers exist to the effective treatment of GBM including the tightly controlled interface between the bloodstream and central nervous system termed the ‘neurovascular unit,’ a narrow and tortuous tumor extracellular space containing a dense meshwork of proteins and glycosaminoglycans, and genomic heterogeneity and instability. A major goal of GBM therapy is achieving sustained drug delivery to glioma cells while minimizing toxicity to adjacent neurons and glia. Targeted nanotherapeutics have emerged as promising drug delivery systems with the potential to improve pharmacokinetic profiles and therapeutic efficacy. Some of the key cell surface molecules that have been identified as GBM targets include the transferrin receptor, low‐density lipoprotein receptor‐related protein, αvβ3 integrin, glucose transporter(s), glial fibrillary acidic protein, connexin 43, epidermal growth factor receptor (EGFR), EGFR variant III, interleukin‐13 receptor α chain variant 2, and fibroblast growth factor‐inducible factor 14. However, most targeted therapeutic formulations have yet to demonstrate improved efficacy related to disease progression or survival. Potential limitations to current targeted nanotherapeutics include: (1) adhesive interactions with nontarget structures, (2) low density or prevalence of the target, (3) lack of target specificity, and (4) genetic instability resulting in alterations of either the target itself or its expression level in response to treatment. In this review, we address these potential limitations in the context of the key GBM targets with the goal of advancing the understanding and development of targeted nanotherapeutics for GBM. WIREs Nanomed Nanobiotechnol 2017, 9:e1439. doi: 10.1002/wnan.1439 This article is categorized under: Therapeutic Approaches and Drug Discovery > Emerging Technologies Therapeutic Approaches and Drug Discovery > Nanomedicine for Neurological Disease Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease
Passive versus active tumor targeting. In an effort to overcome barriers to the treatment of glioblastoma (GBM), nanotherapeutics designed for either passive or active tumor targeting have emerged as a promising approach. Although the blood brain barrier (BBB) is altered in the tumor core, it remains largely intact in regions where tumor cells have infiltrated healthy brain parenchyma, thereby hindering systemic therapeutic delivery to the invasive GBM cells that are largely responsible for tumor recurrence after initial surgical resection. Actively targeted nanotherapeutics—designed to kill those GBM cells left behind after surgical resection, but not healthy human brain cells—have the potential to improve pharmacokinetic profiles and therapeutic efficacy.
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In vivo distribution of nontargeted and Fn14‐targeted polystyrene nanoparticles 24 h following intracranial injection into a mouse bearing a U87/green fluorescent protein (GFP) cell intracranial tumor. Representative distribution of (a) nontargeted PEG‐coated nanoparticles (light blue), (b) ITEM4‐conjugated PEG‐coated nanoparticles (red), and (c) GFP‐expressing U87 tumors (green) in mouse striatum using fluorescence microscopy. (d) Merged image where colocalization between Fn14‐targeted nanoparticles and GFP‐expressing U87 tumor cells is shown in yellow. (Reprinted with permission from Ref . Copyright 2015 Elsevier)
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Immunohistochemical analysis of Fn14 protein expression in normal human brain and glioblastoma (GBM) tissue. Non‐neoplastic brain tissue from a 31 year old male epilepsy patient (a) and tumor tissue from a 77 year old female patient with a right parietoccipital GBM (b) was immunostained using an anti‐Fn14 antibody. Fn14 protein (brown stain) was detected in glioma cells but not in non‐neoplastic tissue. Scale bar = 200 µm.
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A schematic representation of the human Fn14 protein is shown. Mature human Fn14 is 102 amino acids (aa) in length, with a predicted molecular mass of 10,925 daltons and a theoretical isoelectric point of 8.24. Abbreviation: TRAF, tumor necrosis factor receptor‐associated factor. (Reprinted with permission from Ref . Copyright 2008 Nature Publishing Group)
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Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease
Therapeutic Approaches and Drug Discovery > Emerging Technologies
Therapeutic Approaches and Drug Discovery > Nanomedicine for Neurological Disease

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