Elsevier

Drug Resistance Updates

Volume 19, March 2015, Pages 1-12
Drug Resistance Updates

Review
Overcoming the blood–brain tumor barrier for effective glioblastoma treatment

https://doi.org/10.1016/j.drup.2015.02.002Get rights and content

Abstract

Gliomas are the most common primary brain tumors. Particularly in adult patients, the vast majority of gliomas belongs to the heterogeneous group of diffuse gliomas, i.e. glial tumors characterized by diffuse infiltrative growth in the preexistent brain tissue. Unfortunately, glioblastoma, the most aggressive (WHO grade IV) diffuse glioma is also by far the most frequent one. After standard treatment, the 2-year overall survival of glioblastoma patients is approximately only 25%. Advanced knowledge in the molecular pathology underlying malignant transformation has offered new handles and better treatments for several cancer types. Unfortunately, glioblastoma multiforme (GBM) patients have not yet profited as although numerous experimental drugs have been tested in clinical trials, all failed miserably. This grim prognosis for GBM is at least partly due to the lack of successful drug delivery across the blood–brain tumor barrier (BBTB). 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. The BBTB encompasses existing and newly formed blood vessels that contribute to the delivery of nutrients and oxygen to the tumor and facilitate glioma cell migration to other parts of the brain. The high metabolic demands of high-grade glioma create hypoxic areas that trigger increased expression of VEGF and angiogenesis, leading to the formation of abnormal vessels and a dysfunctional BBTB. Even though the BBTB is considered ‘leaky’ in the core part of glioblastomas, in large parts of glioblastomas and, even more so, in lower grade diffuse gliomas the BBTB more closely resembles the intact blood–brain barrier (BBB) and prevents efficient passage of cancer therapeutics, including small molecules and antibodies. Thus, many drugs can still be blocked from reaching the many infiltrative glioblastoma cells that demonstrate ‘within-organ-metastasis’ away from the core part to brain areas displaying a more organized and less leaky BBTB. Hence, drug delivery in glioblastoma deserves explicit attention as otherwise new experimental therapies will continue to fail. In the current review we highlight different aspects of the BBTB in glioma patients and preclinical models and discuss the advantages and drawbacks of drug delivery approaches for the treatment of glioma patients. We provide an overview on methods to overcome the BBTB, including osmotic blood–brain barrier disruption (BBBD), bradykinin receptor-mediated BBTB opening, inhibition of multidrug efflux transporters, receptor-mediated transport systems and physiological circumvention of the BBTB. While our knowledge about the molecular biology of glioma cells is rapidly expanding and is, to some extent, already assisting us in the design of tumor-tailored therapeutics, we are still struggling to develop modalities to expose the entire tumor to such therapeutics at pharmacologically meaningful quantities. Therefore, we must expand our knowledge about the fundamentals of the BBTB as a step toward the design of practical and safe devices and approaches for enhanced drug delivery into the diseased brain area.

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.

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