Tumor-targeted nanotherapeutics: overcoming treatment barriers for glioblastoma.
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, αvβ3integrin, 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.
Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, MD, USA.|Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA.
Aniket S
AS
Wadajkar
Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, MD, USA.|Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA.
Jimena G
JG
Dancy
Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, MD, USA.
David S
DS
Hersh
Department of Diagnostic Radiology and Nuclear Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.
Pavlos
P
Anastasiadis
Departments of Cancer Biology and Neurosurgery, Mayo Clinic Arizona, Scottsdale, AZ, USA.
Nhan L
NL
Tran
Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, MD, USA.|Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA.
Graeme F
GF
Woodworth
Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA.|Department of Surgery, University of Maryland School of Medicine, Baltimore, MD, USA.|Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, MD, USA.
Jeffrey A
JA
Winkles
Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, MD, USA.|Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA.|Department of Pharmacology, University of Maryland School of Medicine, Baltimore, MD, USA.|Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MD, USA.|Center for Biomedical Engineering and Technology, University of Maryland School of Medicine, Baltimore, MD, USA.
Anthony J
AJ
Kim
D000970:Antineoplastic Agents / Q000008:administration & dosage*; D001932:Brain Neoplasms / Q000188:drug therapy*; D016503:Drug Delivery Systems; D005909:Glioblastoma / Q000188:drug therapy*; D006801:Humans; D050997:Nanomedicine; D053758:Nanoparticles / Q000737:chemistry*
D000970:Antineoplastic Agents