Brain drug targeting: Linker strategies: the engineering of multifunctional drug formulations

From time to time, this journal will publish reviews of exceptional textbooks and monographs for an Bessential bookshelf^ of neuropharmacology. No books better exemplify this goal than the 2 texts reviewed below. Together, they bring into sharp focus contemporary drug development for the central nervous system (CNS). William Pardridge_s text deals with the challenges in creating effective CNS therapeutics beyond conventional options of, typically, lipidsoluble molecules smaller than 500 d. Subtitled The Future of Brain Drug Development, this volume is a thorough exposition of the many ways that drugs of various characteristics can be delivered to their intended targets. Dr Pardridge, professor of medicine at UCLA and a distinguished authority on the bloodbrain barrier, has created an especially clear summary comprising decades of research, much of it his own. (His 1998 text on blood-brain barrier physiology is also a classic.) In the 10 clearly organized and richly illustrated chapters of BBrain Drug Targeting,^ he has detailed the many tools available for getting a variety of therapeutic and diagnostic agents into the brain. Approximately 800 references are cited. The text provides a number of examples of how the blood-brain barrier has been breached, but these detailed examples do not overshadow the clarity of expositionV this is a text meant to educate by emphasizing concepts and insights from research conducted in animal studies and awaiting human applications. Dr Pardridge provides thorough and cogent discussions of key physiological properties underlying the bloodbrain barrier and how to traverse it. Among potential carrier systems described are cationized albumin and other endogenous proteins such as insulin and transferrin. The goals of using such carrier proteins are to mimic and capitalize on the abilities of these proteins to cross the blood-brain barrier linked to pharmaceuticals. Other vectormediated delivery proteins, such as carboxyl-directed protein pegylation, are reviewed, along with the creation of cleavable and noncleavable carriers with monoclonal antibodies. Successive chapters deal with a wide range of drug delivery options, such as direct intrathecal drug administration, osmoticmedicated and cytokine-medicated blood-brain barrier disruption, liposome carrier systems, and chimeric peptide technology for using transcytosis (such as avidin-biotin complexes). The text also considers principles governing how various radiopharmaceuticals and neurotrophic factors (such as brain-derived neurotrophic factor) might be sent into the brain for imaging and therapeutic purposes. As set out in the introduction, the goal of promoting the entrance into CNS of larger and more complex molecules is clearly the challenge of neuropharmacology in the 21st century. I know of no better starting point for understanding how progress in neurotherapeutics will be made than in the 352 pages of Brain Drug Targeting. Another superlative text on CNS drug development is a 319-page monograph by Franz Hefti, now an insider in pharmaceutical industry drug development and formerly a leading laboratory researcher into the therapeutics of neurodegenerative disorders. Over the years, rational therapeutics for CNS disorders has arrived only in meager quantities, although the pace has been increasing with new technologies such as proteonomic analysis and transgenic animals for genetic disorders. Dr Hefti takes stock of the process and the challenges ahead from the perspective of industry, government programs, and the practical elements of clinical research. His book is organized by the various CNS disorders awaiting better treatment, among them depression, anxiety disorders, schizophrenia, neurodegenerative disorders (especially Parkinson and Alzheimer diseases), epilepsy, stroke, pain, and CNS injury. This text details the process of translational research bringing laboratory advances into clinical trials. Amidst the enthusiasms of scientists and the frustrations of patients, the pharmaceutical industry needs to proceed along circumscribed pathways to design and implement the much-needed drugs. Dr Hefti provides an overview of the drug development process along with many examples of success and failures. He offers detailed neurochemical background for the rationale behind most of today_s neurotherapeutics. One insight described in the text is that there are no more than 17 validated targets of drug interventions in the CNS, although there are many other uncharacterized examples of drug effects. This volume is not written at the same level of complexity as the Pardridge text, but it contains a wealth of information, and its message is authoritative on contemporary pathways for drug exploration and development. Each chapter contains key references and suggestions for further reading. Thorough reviews of all available classes of neuropharmacological interventions are provided, starting with their history, the physiological targets of intervention, animal models, and laboratory methods such as reverse pharmacology and metabolomics. Much of the optimism behind the targeting of drugs for nervous system diseases has been the 4-decade reign of levodopa and other successful symptomatic treatments for Parkinson_s disease. At the end of his 1817 monograph An Essay on the Shaking Palsy, James Parkinson, MD, provided a 19th-century perspective that, until recently, might apply also to a number of neurological and psychiatric disorders: