Overcoming the blood brain barrier in glioblastoma: Status and future perspective

Glioblastoma (GBM) is the most common and the deadliest primary brain cancer in adults. Approximately three new cases are diagnosed per 100,000 inhabitants each year [1]. The standard of care (SOC) of newly diagnosed glioblastoma patients relies on maximal safe surgery followed by concurrent radio-chemotherapy and adjuvant chemotherapy with temozolomide, an alkylating agent. In subgroups of patients, addition of lomustine or tumor-treating fields is recommended in addition to the SOC [2], [3]. Despite this very intensive therapeutic regimen, the median overall survival of glioblastoma patients is between 12 and 18 months [4], [5].

Glioblastoma cells are resistant to treatments. Multiples mechanisms are involved in treatment resistance including the blood-brain barrier (BBB) and its role in limiting drug penetration and drug efficacy within the normal brain and the tumor [6].

Indeed, although the BBB is partially disrupted in glioblastoma, it is intact in the bed around the tumor where invasive cells are located. These invasive cells, protected against therapeutic agents by the intact BBB, are often the source of resistance to treatments and the source of tumor recurrence [7]. In the bed around the tumor, only 20% of small molecules and no large therapeutics agents cross the BBB and reach tumor cells at a therapeutic dose level [8].

The BBB is both a biophysical and a biochemical barrier. Indeed, the BBB includes from the lumen of brain vessel to the brain parenchyma, forming a biophysical barrier:

endothelial cells;

pericytes;

extracellular matrix and;

astrocyte end-feet.

In addition to these biophysical properties of the BBB, several biochemical pathways govern the passage, through the BBB, of therapeutic and non-therapeutic molecules from the blood stream to the brain parenchyma based on their characteristics (i.e., size, liposolubility, electric charge, interactions with blood proteins, and interactions with BBB proteins) (Fig. 1). Besides the proprieties of the BBB, blood pressure is also involved in a drug's ability to cross the BBB [9] (Fig. 2).

Overall, the BBB is a major obstacle for drug penetration within the brain parenchyma in the setting of central nervous system diseases including brain cancers and glioblastomas. Therefore, several strategies have been proposed and are continuously being developed to overcome, to circumvent, to bypass, or to disrupt the BBB, aiming toward better drug bioavailability within the pathological brain. In this review, we will discuss the strategies that are currently under investigation in clinical trials to increase brain drug delivery (via systemic and local routes) and strategies increasing drug penetration (via drug or BBB modulation).

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