Targeting the Brain
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REVIEW PAPER
Targeting the Brain Rationalizing the novel methods of drug delivery to the central nervous system Shailendra Joshi Æ Eugene Ornstein Æ Jeffrey N. Bruce
Published online: 20 April 2007 Humana Press Inc. 2007
Abstract Drug delivery to the brain has remained one of the most vexing problems in translational neuroscience research. This review rationalizes the strategies to target drugs to the brain. Factors such as the speed of intervention, the scale of intervention, the state of BBB, and the permissible risks, will all be critical in deciding how best to deliver drugs to a target site in the brain for a specific clinical situation. Keywords Cerebral Regional Selective Pharmacokinetics
Introduction Drug delivery to the brain has remained one of the most vexing problems in translational neuroscience research [1, 2]. Many therapies that have been effective in laboratory settings have failed in clinical trials. Yet, each day promising treatments of brain diseases emerge from laboratories across the country. The clinical impact of these innovative treatments will go unrealized unless effective means of drug delivery are concurrently developed. The anatomical, physiological, and functional characteristics of the brain challenge the imagination of investigators who
S. Joshi (&) E. Ornstein Department of Anesthesiology, College of Physicians and Surgeons of Columbia University, 630 West 168th Street, P&S Box 46, New York, NY 10032, USA e-mail: [email protected] J. N. Bruce Department of Neurosurgery, College of Physicians and Surgeons of Columbia University, New York, NY 10032, USA
are developing novel methods of brain selective drug delivery. This review describes the salient features of technologies aimed at delivering drugs to the brain and rationalizes their use in the context of their clinical applications. The approaches to target drugs to the central nervous system (Fig. 1) can be classified as: 1. Direct delivery, generally bypassing the blood brain barrier (BBB): Direct injection, convection enhanced delivery, biodegradable delivery systems (polymer wafers, nanoparticles, liposomes), as well as, intrathecal and intraarterial injections. 2. Enhanced delivery across an intact BBB: Non-specific mechanism: Manipulation of lipid solubility. Specific mechanisms: Receptor mediated and adsorptive transcytosis, modulation of transport systems, e.g., p-gap. 3. Targeting technologies: Methods to increase local concentrations of drugs in the brain after systemic delivery, which include magnetic and immunological targeting, as well as, ultrasound assisted drug release. Anatomical and physiological concerns Compared to other animal species, the brain size of the humans is much greater in proportion to the total body weight [3]. Large brain weight relative to the body size, directly affects the dose requirements. Intraarterial doses of carmustine, that are toxic to dogs, are safely tolerated by humans and non-human primates [4]. Compared to other organs, the human brain also receives a greater share of
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