Dr. Jain is a consultant in neurology and has no relevant financial relationships to disclose.)
The delivery of drugs to the brain is a challenge in the treatment of CNS disorders. The major obstruction to CNS drug delivery is the blood-brain barrier, which limits the access of drugs to the brain substance. This article describes various strategies to facilitate drug delivery to the brain in neurologic disorders. Most of these involve methods to penetrate the blood-brain barrier or to bypass it. Gene therapy is a novel form of drug delivery. Special preparation of drugs used for neurologic disorders can provide controlled and improved delivery to the site of action. The latest among these are nanoparticle-based preparations.
• Treatment of CNS disorders is limited by difficulties in drug delivery to the site of action.
• Several methods have been used to deliver drugs directly to the brain.
• Important strategies include facilitation of passage of systemically administered drugs across the blood-brain barrier.
• New technologies such as nanobiotechnology are improving drug delivery to the CNS.
Historical note and terminology
The delivery of drugs to the brain is a challenge in the treatment of CNS disorders. The major obstruction to CNS drug delivery is the blood-brain barrier, which limits the access of drugs to the brain substance. In the past, treatment of CNS disease was done mostly with systemically administered drugs. This trend continues. Most CNS-disorder research is directed toward the discovery of drugs and formulations for controlled release; little attention has been paid to the method of delivery of these drugs to the brain.
Although the cerebral ventricles were tapped for hydrocephalus in ancient times, the first perforation of subarachnoid space by lumbar puncture was made in 1885 to administer cocaine for anesthesia (Corning 1885). The concept of the blood-brain barrier was described in the same year by Paul Ehrlich when he observed that dyes injected into the vascular system were rapidly taken up by all the organs except the brain (Ehrlich 1885). Later, it was shown that dyes injected into the cerebrospinal fluid have free access to the neural tissues but do not enter the blood supply of the brain. The transient opening or disruption of the blood-brain barrier after intracarotid arterial administration of hypertonic solutions was first observed by Broman in 1941 (Broman 1941). The first injections into the cerebral circulation were of contrast materials for cerebral angiography (Moniz 1927). The injection of a therapeutic substance (diazepam) into the carotid arteries was not reported until 25 years ago (Doppman 1973).
The advent of stereotactic surgery 50 years ago opened the way for placing instruments at selected targets in the depth of the brain for the treatment of movement disorders (Spiegel et al 1947). This approach was used some years later to perform chemopallidectomy by injecting a mixture of procaine and alcohol into the globus pallidus (Cooper 1954). The techniques of creating lesions in basal ganglia have been refined, but these principles of localization and injection have been used for the introduction of novel therapeutic agents into the brain for the treatment of movement disorders. The first implantable pump for intrathecal and intraventricular injection of morphine for the treatment of cancer pain was described in 1978 (Lazorthes et al 1991). Chromaffin cell grafts have been introduced into the spinal subarachnoid space by lumbar puncture for long-term relief of intractable cancer pain. A phase II open study demonstrated the feasibility and the safety of this approach (Lazorthes et al 2000). However, this technique was never introduced into clinical practice.
Further progress has taken place with the development of intra-arterial chemotherapy, direct injections of therapeutic substances into intracranial lesions, and strategies to overcome the blood-brain barrier. Use of nanoparticles for drug delivery across the blood-brain barrier has significantly improved the techniques for drug delivery to the brain.
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