Modulating the Blood-Brain Barrier: A Comprehensive Review

Abstract

The highly secure blood-brain barrier (BBB) restricts drug access to the brain, limiting the molecular toolkit for treating central nervous system (CNS) diseases to small, lipophilic drugs. Development of a safe and effective BBB modulator would revolutionise the treatment of CNS diseases and future drug development in the area. Naturally, the field has garnered a great deal of attention, leading to a vast and diverse range of BBB modulators. In this review, we summarise and compare the various classes of BBB modulators developed over the last five decades-their recent advancements, advantages and disadvantages, while providing some insight into their future as BBB modulators.

Keywords: BBB modulation; BBB permeability; CNS drug delivery; alzheimers; blood-brain barrier (BBB); focused ultrasound; glioblastoma; hyperosmolar agents; intra-arterial drug delivery; tight junction (TJ).

Figure 1

The healthy blood–brain barrier. The blood–brain barrier is comprised primarily of brain microvascular endothelial cells (BMECs) which create a physical barrier, arising through the formation of tight junctions at endothelial cell interfaces by claudins, occludin and junctional adhesion molecules. The formation of tight junctions restricts paracellular flux greatly while high expression of efflux proteins on the endothelial luminal surface hinders passive transcellular diffusion. In addition to BMECs, the BBB is comprised of astrocytes and pericytes. These cells provide less structural support with regard to BBB formation and function primarily in barrier regulation. Pericytes possess a broad range of functions in vascular regulation [15], while astrocytes provide a cellular link between the nervous tissue and the vascular system [16,17]. The organisation of these cell types forms the neurovascular unit, which is the building block that makes up the BBB. Abbreviations: BCRP (breast cancer resistance protein), OAT3 (organic anion transporter 3), P-Gp (P-glycoprotein), ZO-1 (zonula occludens-1).

Figure 2

Success rates of clinical trial phases categorised by disease type from 2010–2017. The CMR R&D Performance Metrics reported the average clinical phase success rate of pharmaceutical drugs that treat the most common disease areas from 2010–2017. Combining the success rate of each phase provides the success rate probability of a drug from phase I to launch. Averaging the combined phase success rates of non-CNS drug categories leads to an average 12-fold greater success rate relative to CNS drugs, highlighting the high failure rate of CNS drug candidates in drug development. Data taken from ref. [19], with additional extrapolations made.

Figure 3

Blood–brain barrier modulation mechanism of focused ultrasound and hyperosmolar agents. Hyperosmolar agents disrupt the blood–brain barrier by dehydrating endothelial cells in the vascular lumen, causing them to contract. The shrinking of the cells leads to the opening of TJ gaps, enabling enhanced and indiscriminate paracellular flow of solutes. Exposure of microbubbles within brain capillaries to ultrasound waves induces rapid expansion and contraction, disrupting the microvascular endothelial cells of the blood–brain barrier and creating cavitation sites at a sensitivity greater than direct FUS. Additionally, the power required to induce blood–brain barrier disruption is lowered by 100-fold, falling below the levels required to damage tissue.

Figure 4

Mechanism summary for blood–brain barrier-modulating small molecules. Small molecules are a diverse category of blood–brain barrier modulators that primarily induce paracellular flux by altering tight junctions via indirect interactions through rearrangement of the cytoskeleton. Abbreviations: AG (alkylglycerol), BCRP (breast cancer resistant protein), β (beta GPCR subunit), γ (gamma GPCR subunit), CAM (calmodulin), DAG (diglyceride), ER (endoplasmic reticulum), FG (fingolimod), G_12/13 (G12/G13 alpha GPCR subunits), G_i (Gi alpha GPCR subunit), G_q (Gq alpha GPCR subunit), IP₃ (inositol triphosphate), IP₃R (inositol triphosphate receptor), MLCK (myosin light chain kinase), NB (NIBR-0213), P-GP (P-glycoprotein), PI3K (phosphoinositide 3-kinase), PIP₂ (phosphatidylinositol 4,5-bisphosphate), PKC (protein kinase C), PLC (phospholipase C), RD (regadenoson), ROCK (Rho-associated protein kinase), SC (sodium caprate), WAVE (WASP-family verprolin homologous protein), ZO-1 (zonula occludens-1).

Figure 5

Mechanism summary for blood–brain barrier-modulating peptides. Similar to small molecule blood–brain barrier modulators, peptides affect tight junction integrity in a diverse manner, either through direct interruption of TJ protein trans interactions or by altering an indirect downstream effector. Abbreviations: αi (Gi alpha GPCR subunit), AC (adenylate cyclase), ADT (ADT-6 or ADTC5), AT (AT-1002), ATP (adenosine triphosphate), β (beta GPCR subunit), B2 (bradykinin receptor 2), γ (gamma GPCR subunit), cAMP (cyclic adenosine monophosphate), DAG (diglyceride), HAV (HAV-6 or cHAVc3), IP₃ (inositol triphosphate), MLCK (myosin light chain kinase), PIP₂ (phosphatidylinositol 4,5-bisphosphate), PLC (phospholipase C), PN (PN-159), RMP (RMP-7).

Figure 6

SiRNA Mechanism for blood–brain barrier modulation. siRNAs are derived from double-stranded RNAs of approximately 21 base pairs in length, that when introduced into a cell induce mRNA degradation for RNA of complementary nucleotide sequences, preventing the translation of a particular gene. siRNA has been used to silence transporters and tight junction proteins to modulate the blood–brain barrier. Abbreviations: AGO2 (protein argonaute-2), OAT3 (organic anion transporter 3), P-Gp (P-glycoprotein), RISC (RNA-induced silencing complex), ZO-1 (zonula occludens1).

Figure 7

Summary of active BBBD clinical trials categorised by modulation method (left) and associated disease investigated (right). Currently 45 active clinical trials involving Blood–brain barrier Disruption are taking place. The majority of these trials are using focused ultrasound technology to facilitate greater efficacy of anticancer drugs to treat various gliomas.