Drug Delivery to the Central Nervous System

Introduction

The effective delivery of pharmaceutical agents into the central nervous system (CNS) still represents a significant challenge to modern drug delivery. Much of this can be attributed to the presence of the blood–brain barrier (BBB), which consists of a network of tight junctions formed between cerebral capillary endothelial cells along with the surrounding basal lamina, astrocytes, pericytes, and microglia. The integrity of these tight junctions is mediated by a number of important proteins such occludins, claudins, cadherins, and a variety of cell adhesion molecules. This dynamic environment is a critical regulator of brain homeostasis and tightly regulates the entry of agents into the CNS. This barrier is thought to allow diffusion of gas molecules, such as O ₂ and CO ₂ and lipophilic small molecules (less than 400 Da) while still being largely impermeable to hydrophilic and macromolecular drugs. However, most lipophilic drugs are plagued by poor pharmacokinetic properties in systemic circulation. Although the use of polymer and lipid-based nanoparticles initially served as an attractive approach to increase the systemic circulation of these drugs, they still remain largely impermeable to the BBB .

In order for therapeutic drugs to be able to affect the CNS, they need to traverse this barrier, and it should also be ensured that there is a sufficient concentration of drug reaching the intended targets. Therefore, a number of interesting strategies have been employed to traverse the BBB by specifically targeting its components, or by simply circumventing the BBB altogether by employing nonsystemic routes, allowing for direct drug distribution into the CNS. These strategies have been reviewed in greater detail in the following discussion.

Crossing the BBB

As mentioned earlier, the effective treatment of brain diseases represents a significant challenge to pharmaceutical research due to their delicate environment. Many approaches aimed at overcoming the BBB to promote drug delivery for the treatment of brain diseases, including neurodegenerative diseases and brain cancer, have been proposed. Some of these approaches involve directly affecting BBB function either due to its temporary disruption by physical means, or by specifically targeting one or more of its biological components.