Breaking Barriers in Neuro-Oncology: A Scoping Literature Review on Invasive and Non-Invasive Techniques for Blood-Brain Barrier Disruption

Abstract

The blood-brain barrier (BBB) poses a significant challenge to drug delivery for brain tumors, with most chemotherapeutics having limited permeability into non-malignant brain tissue and only restricted access to primary and metastatic brain cancers. Consequently, due to the drug's inability to effectively penetrate the BBB, outcomes following brain chemotherapy continue to be suboptimal. Several methods to open the BBB and obtain higher drug concentrations in tumors have been proposed, with the selection of the optimal method depending on the size of the targeted tumor volume, the chosen therapeutic agent, and individual patient characteristics. Herein, we aim to comprehensively describe osmotic disruption with intra-arterial drug administration, intrathecal/intraventricular administration, laser interstitial thermal therapy, convection-enhanced delivery, and ultrasound methods, including high-intensity focused and low-intensity ultrasound as well as tumor-treating fields. We explain the scientific concept behind each method, preclinical/clinical research, advantages and disadvantages, indications, and potential avenues for improvement. Given that each method has its limitations, it is unlikely that the future of BBB disruption will rely on a single method but rather on a synergistic effect of a combined approach. Disruption of the BBB with osmotic infusion or high-intensity focused ultrasound, followed by the intra-arterial delivery of drugs, is a promising approach. Real-time monitoring of drug delivery will be necessary for optimal results.

Keywords: blood–brain barrier; blood–tumor barrier; convection-enhanced delivery; focused ultrasound; laser interstitial thermal therapy; low-intensity pulsed ultrasound; osmotic disruption; tumor-treating fields.

Figure 3

The BBB and neurovascular unit. (A) In a cross-sectional view of a mouse cortical capillary, the endothelium appears highly attenuated, featuring small branches of pericytes on its abluminal surface. (B) The BBB is composed of the capillary endothelial cells with their tight junctions and underlying pericytes, both surrounded by an amorphous basement membrane (BM) and astrocytic end-feet. Ast, astrocyte; De, dendrite. Reused from Nahirney et al. [38].

Figure 1

Flow diagram demonstrating the process of article selection.

Figure 2

Depicts the BBB’s structure and transport mechanisms. The BBB’s structure consists of brain microvessels involving pericytes, endothelial cells, astrocytes, and neurons. Mechanisms for transport across the BBB include the following: diffusion (transcellular lipophilic pathway), carrier-mediated transport (CMT), receptor-mediated endocytosis (RME), absorption-mediated endocytosis (AME), proton pump, cell-mediated transport, and paracellular waterway. Reused from Mitusova et al. [29].

Figure 4

Differences in structure between the BBB (a) and BTB (b). The BBB consists of a monolayer of non-fenestrated endothelial cells connected by tight junctions. It involves interaction with astrocyte foot processes and pericytes, along with the presence of a functional basement membrane. As the tumor progresses, invasive cells provoke architectural changes in the normal brain vasculature, resulting in fenestrated endothelial cells, disrupted basement membrane (basal lamina), and unattached astrocytes and pericytes. The BTB is also characterized by increased pinocytic activity. Reused from Qiu et al. [48].

Figure 5

The difference between fast and slow infusion rates during SIACI and their impact on drug delivery. Courtesy of the Society of Image-guided Neurointerventions (SIGN).

Figure 6

Demonstrates the perfusion-guided endovascular super-selective intra-arterial infusion workflow proposed by Chen et al.: (A) Alignment of patient position with MRI. (B) Three-dimensional (3D) overlay for vessel selection. (C) Integration of parenchymal blood volume (PBV) with MRI. Reused with permission from Chen et al. [111].

Figure 7

An intratumoral placement of laser catheter and brain tumor ablation. Brain tumor ablation showing post-LITT contrast enhancement consistent with LITT-related BBB disruption and LITT-related perifocal edema. Reused from Skandalakis et al. [122].