title: Emerging insights into barriers to effective brain tumor therapeutics.
abstract: There is great promise that ongoing advances in the delivery of therapeutics to the central nervous system (CNS) combined with rapidly expanding knowledge of brain tumor patho-biology will provide new, more effective therapies. Brain tumors that form from brain cells, as opposed to those that come from other parts of the body, rarely metastasize outside of the CNS. Instead, the tumor cells invade deep into the brain itself, causing disruption in brain circuits, blood vessel and blood flow changes, and tissue swelling. Patients with the most common and deadly form, glioblastoma (GBM) rarely live more than 2 years even with the most aggressive treatments and often with devastating neurological consequences. Current treatments include maximal safe surgical removal or biopsy followed by radiation and chemotherapy to address the residual tumor mass and invading tumor cells. However, delivering effective and sustained treatments to these invading cells without damaging healthy brain tissue is a major challenge and focus of the emerging fields of nanomedicine and viral and cell-based therapies. New treatment strategies, particularly those directed against the invasive component of this devastating CNS disease, are sorely needed. In this review, we (1) discuss the history and evolution of treatments for GBM, (2) define and explore three critical barriers to improving therapeutic delivery to invasive brain tumors, specifically, the neuro-vascular unit as it relates to the blood brain barrier, the extra-cellular space in regard to the brain penetration barrier, and the tumor genetic heterogeneity and instability in association with the treatment efficacy barrier, and (3) identify promising new therapeutic delivery approaches that have the potential to address these barriers and create sustained, meaningful efficacy against GBM.
authors.affiliation: Department of Neurosurgery, University of Maryland School of Medicine , Baltimore, MD , USA ; Department of Anatomy and Neurobiology, University of Maryland School of Medicine , Baltimore, MD , USA.
authors.forename: Graeme F
authors.initials: GF
authors.lastname: Woodworth
authors.affiliation: Department of Neurosurgery, Pathology and Immunology, Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine , St. Louis, MO , USA.
authors.forename: Gavin P
authors.initials: GP
authors.lastname: Dunn
authors.affiliation: Center for Nanomedicine, Johns Hopkins University School of Medicine , Baltimore, MD , USA.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Nance
authors.affiliation: Center for Nanomedicine, Johns Hopkins University School of Medicine , Baltimore, MD , USA ; Department of Ophthalmology, Johns Hopkins University School of Medicine , Baltimore, MD , USA ; Department of Neurosurgery, Johns Hopkins University School of Medicine , Baltimore, MD , USA.
authors.forename: Justin
authors.initials: J
authors.lastname: Hanes
authors.affiliation: Department of Neurosurgery, Johns Hopkins University School of Medicine , Baltimore, MD , USA.
authors.forename: Henry
authors.initials: H
authors.lastname: Brem
keywords: advanced therapeutics; blood brain barrier; brain cancer; drug delivery; glioblastoma; immunotherapy; nanomedicine; nanotechnology
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