Abstract
Here, we present a brief review of brain-targeting chemical delivery systems (CDSs) and their cyclodextrin-based formulations. It is dedicated to the memory of Marcus E. Brewster (1957-2014) and highlights those aspects where he made particularly valuable contributions. During the first two decades of his scientific career that were dedicated to these fields (1978-1997), Marcus was involved in the development of several brain-targeted redox compounds, including design, activity assays, physicochemical characterization, computational modeling of theoretical aspects, and development of cyclodextrin-based formulation for increased stability and water solubility, as well as preclinical and clinical testing. CDSs are designed to provide site-specific or site-enhanced delivery through sequential, multistep enzymatic, and chemical transformations. Brain-targeting CDSs incorporate a redox targetor that undergoes enzymatic transformation resulting in a drastic change in physicochemical properties. They can not only increase central nervous system access by making the molecule more lipophilic and enabling its diffusion through the blood-brain barrier, but they can also provide more sustained release by “locking” it behind the blood-brain barrier by subsequently converting it into a hydrophilic intermediate. The origins of the concept (Pro-2-PAM, berberine), one of the most important representative (estradiol-CDS), and the introduction of 2-hydroxypropyl-b-cyclodextrin for improved formulations are discussed in detail.
Introduction
To honor the contributions that Dr. Marcus E. Brewster (October 14, 1957 to September 15, 2014) made to the progress of pharmaceutical sciences as reflected by his about 75 patents and more than 270 publications,1 here we will review basic aspects of the redox brain-targeting chemical delivery systems (CDSs) and their cyclodextrin (CD)-based formulations, highlighting those parts where Marcus made particularly valuable contributions. He worked on these for more than 2 decades, first as a graduate student and then, after defending his thesis in 1982,2 as a postdoc at the University of Florida. He continued to work on them as Director of Research at a startup company (Pharmatec) before moving on to become Director of Drug Delivery Research at Janssen Pharmaceutica in 1997. During this time, hewas involved in the design and development of several brain-targeted redox compounds, and his contributions covered many areas including design, activity assays, characterization of physicochemical aspects, computational modeling, and development of CD-based formulation for increased stability and water solubility, as well as preclinical and clinical testing. Marcus contributed prolifically to these areas as illustrated by his more than 130 publications on these subjects co-authored with the senior author of this review (N.B.).