The influence of the blood–brain barrier in the treatment of brain tumours

Abstract

Brain tumours have a poor prognosis and lack effective treatments. The blood-brain barrier (BBB) represents a major hurdle to drug delivery to brain tumours. In some locations in the tumour, the BBB may be disrupted to form the blood-brain tumour barrier (BBTB). This leaky BBTB enables diagnosis of brain tumours by contrast enhanced magnetic resonance imaging; however, this disruption is heterogeneous throughout the tumour. Thus, relying on the disrupted BBTB for achieving effective drug concentrations in brain tumours has met with little clinical success. Because of this, it would be beneficial to design drugs and drug delivery strategies to overcome the 'normal' BBB to effectively treat the brain tumours. In this review, we discuss the role of BBB/BBTB in brain tumour diagnosis and treatment highlighting the heterogeneity of the BBTB. We also discuss various strategies to improve drug delivery across the BBB/BBTB to treat both primary and metastatic brain tumours. Recognizing that the BBB represents a critical determinant of drug efficacy in central nervous system tumours will allow a more rapid translation from basic science to clinical application. A more complete understanding of the factors, such as BBB-limited drug delivery, that have hindered progress in treating both primary and metastatic brain tumours, is necessary to develop more effective therapies.

Tumor Treating Fields (TTFields) Reversibly Permeabilize the Blood–Brain Barrier In Vitro and In Vivo

“…Although various techniques have been developed to overcome the BBB and enable drug delivery, such as physical modalities (e.g., FUS and PEFs) [ 47 , 48 , 49 ], enhanced lipid- and water-solubility through drug design, as well as employing carriers and vectors [ 50 , 51 , 52 ], these strategies still fall short in outcomes. For instance, it has been reported that issues with reproducibility of FUS procedures can be an obstacle to its clinical use [ 53 ]. Mannitol, a cell-impermeable nontoxic alcohol, has been used successfully for reversible opening of the BBB in hyperosmotic concentrations, both experimentally and clinically [ 50 , 51 , 52 ].…”

Mutated Isocitrate Dehydrogenase (mIDH) as Target for PET Imaging in Gliomas

“…For example, a common reason for the failure of PET neurotracers is limited brain entry due to low passive permeability and/or active export across the blood–brain barrier (BBB). In gliomas, the BBB is often partly disrupted, which results in increased permeability to hydrophilic contrast agents and enables tumor visualization by contrast-enhanced MRI [ 52 , 53 ]. However, BBB disruption shows significant intra- and inter-tumoral heterogeneity, and increased uptake of hydrophilic contrast agents is not necessarily predictive of the accumulation of lipophilic drugs or PET tracers [ 52 , 53 ].…”

Metal-Based Nanostructured Therapeutic Strategies for Glioblastoma Treatment—An Update

“…The BBTB, which is an abnormal, fenestrated and heterogenous variant of the BBB, permits the passage of contrast agents (allowing magnetic resonance imaging of GBM), although the permeability of drugs varies. It is assumed that the BBTB may support drug influx at the site of the tumor; nevertheless, it has also been shown that the accumulation of chemotherapeutics is often irregular, therefore limiting the efficacy of treatment [ 45 , 46 ]. Some of the proposed methods of overcoming this barrier include the usage of focused ultrasound techniques and microbubbles for mechanical opening of the BBB.…”