Tumor-targeted nanotherapeutics: overcoming treatment barriers for glioblastoma

Abstract

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, α_v β₃ 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 For further resources related to this article, please visit the WIREs website.

Figure 1

Passive versus active tumor targeting. In an effort to overcome barriers to treatment of GBM, nanotherapeutics designed for either passive or active tumor targeting have emerged as a promising approach. Although the 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.

Figure 2

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, TNF receptor associated factor. Reprinted from Winkles [130] with permission from the Nature Publishing Group.

Figure 3

Immunohistochemical analysis of Fn14 protein expression in normal human brain and 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.

Figure 4

In vivo distribution of non-targeted and Fn14-targeted polystyrene nanoparticles 24 hours following intracranial injection into a mouse bearing a U87/GFP cell intracranial tumor.. Representative distribution of (A) non-targeted 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 co-localization between ITEM4-conjugated PEG-coated nanoparticles and GFP-expressing U87 tumor cells is shown in yellow. Reprinted from Schneider et al. [49] with permission from Elsevier.