ReviewOvercoming the blood–brain tumor barrier for effective glioblastoma treatment
Section snippets
Gliomas
Gliomas account for approximately 80% of all tumors arising in brain tissue, with an incidence of about 7 per 100,000 individuals worldwide. Patients with gliomas may present with several neurological symptoms such as headaches, seizures, focal neurologic deficits, memory loss, personality changes, vomiting, and visual changes (Chandana et al., 2008, Ferguson, 2011, Wen and Kesari, 2008). According to the World Health Organization (WHO), gliomas are classified according to their cell type and
Molecular composition of the BBB and implications for drug entry
The human brain comprises over 100 billion capillaries with a total length of 400 miles, a total surface area of 20 m2 and a median inter-capillary distance of about 50 μm, making it the best perfused organ in the body (Pardridge, 2005). Proper function of the vasculature in the central nervous system (CNS) is essential for adequate brain function, not only to efficiently supply the brain with nutrients and oxygen, but also to protect the brain from potentially neurotoxic compounds. This
The blood–brain tumor barrier (BBTB)
The functioning and organization of the BBB can be altered under pathological conditions, such as multiple sclerosis, epilepsy, autoimmune deficiency syndrome (AIDS), dementia, stroke, and brain cancer (Abbott et al., 2006, de Vries et al., 2012, Obermeier et al., 2013). Importantly, alterations in the barrier evoked by tumors in the brain do not link with tumor size, tumor type, or anatomic location and is variable within any single neoplasm (Fig. 1) (Groothuis et al., 1984). In low-grade
Circumventing or overcoming the BBTB
During the last decades numerous strategies to improve the delivery of agents to brain tumors have been under investigation (Fig. 2B). Unfortunately, major changes in the landscape of brain tumor therapy have not yet matured from these efforts. In this section, we will briefly discuss the history, pitfalls and potential of developed methodologies.
Future directions
Effective treatment of glioma is hampered by the presence of the BBTB. Especially in areas where the BBTB more closely resembles the BBB, anti-cancer drugs are denied access to the CNS and the tumor cells that reside therein. In this review, we presented a comprehensive synopsis of all the – also clinically applied – approaches used to date to enhance the permeability of the BBTB. While our knowledge about the molecular biology of glioma cells is rapidly expanding and is, to some extent,
Conflict of interest statement
Olaf van Tellingen is co-inventor on a patent application (Bunt and Van Tellingen, 2014) dealing with development of an improved oral formulation for elacridar.
Acknowledgements
This work was supported by the VIDI fellowship 91711366 (T.W.) from the Dutch Organization of Scientific Research (NWO), European Research Council Starting Researchers Grant 336540 (T.W), and Stichting Stophersentumoren.nl (T.W., O.v.T.).
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These authors contributed equally to this work.