Addressing BBB Heterogeneity: A New Paradigm for Drug Delivery to Brain Tumors

Abstract

Effective treatments for brain tumors remain one of the most urgent and unmet needs in modern oncology. This is due not only to the presence of the neurovascular unit/blood-brain barrier (NVU/BBB) but also to the heterogeneity of barrier alteration in the case of brain tumors, which results in what is referred to as the blood-tumor barrier (BTB). Herein, we discuss this heterogeneity, how it contributes to the failure of novel pharmaceutical treatment strategies, and why a "whole brain" approach to the treatment of brain tumors might be beneficial. We discuss various methods by which these obstacles might be overcome and assess how these strategies are progressing in the clinic. We believe that by approaching brain tumor treatment from this perspective, a new paradigm for drug delivery to brain tumors might be established.

Keywords: BTB; NVU/BBB; blood-brain barrier; brain metastases.

Figure 1

The neurovascular unit/blood–brain barrier (NVU/BBB) is composed of specialized endothelial cells and support cells, including pericytes and astrocytes. The cross-sectional view illustrates that the majority of the abluminal surface of the endothelial cell is covered by pericytes and astrocytic foot processes. Paracellular transport across the BBB/NVU is restricted by tight junction proteins, and even small, lipophilic molecules that might diffuse across the BBB may be subject to active efflux by a variety of proteins. Facilitated active transport, receptor-mediated transport, and ion transporters allow the brain to be supplied with nutrients while maintaining strict homeostasis.

Figure 2

The blood–tumor barrier (BTB) is characterized by increased cytokine and VEGF signaling from the tumor, which may lead to decreased expression of tight junction (TJ) proteins like claudin-5. Alterations in pericyte phenotype and disruption of astrocytic associations with endothelial cells may contribute to decreased barrier integrity. However, this is not a uniform phenomenon within or among tumors, and the expression of efflux transporters limits drug permeation into the tumor. Evidence exists showing decreased permeability of the BTB in regions distant to the core of the tumor, which more closely resemble “unaffected” brain.

Figure 3

Various invasive technologies to increase drug delivery to the brain by bypassing the BBB/NVU include intrathecal injection via a lumbar puncture and various intracranial techniques. These include (A) intracerebroventricular injection using the Ommaya reservoir, (B) convection-enhanced delivery (CED) by way of intracerebral catheter placement, and (C) placement of drug-loaded polymeric wafers.

Figure 4

Drug delivery to the brain may be increased by noninvasive BBB disruption (BBBD) techniques, including (A) osmotic disruption and (B) focused ultrasound. In osmotic disruption, infusion of a hyperosmolar solution via a cerebral artery results in endothelial cell shrinkage, temporarily disrupting tight junctions. Focused ultrasound uses an infusion of inert gas-filled microbubbles, which, upon application of focused ultrasound, may burst and temporarily disrupt tight junction proteins. Advantages and disadvantages of both are listed.

Figure 5

Receptor-mediated transcytosis is one of the most common techniques to increase the delivery of large molecules, nanoparticles, and brain-impermeant drugs to brain tumors. Cargo bound to endothelial-membrane-bound receptors is pulled into endothelial cells (ECs) and sorted in the early endosome. Bivalent-binding and high-affinity cargo-receptor complexes are often trafficked to the lysosome for degradation, whereas cargoes bound with lower affinity are more likely to be trafficked for transport across the cell. The cargo is then released on the abluminal side of the endothelium, and the receptor may be recycled back to the luminal membrane.