title: Brain-Targeting Chemical Delivery Systems and Their Cyclodextrin-Based Formulations in Light of the Contributions of Marcus E. Brewster.
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-β-cyclodextrin for improved formulations are discussed in detail.
authors.affiliation: Diabetes Research Institute, University of Miami, Coral Gables, Florida 33146; Department of Molecular and Cellular Pharmacology, University of Miami, Coral Gables, Florida 33146. Electronic address: pbuchwald@med.miami.edu.
authors.forename: Peter
authors.initials: P
authors.lastname: Buchwald
authors.affiliation: Bodor Laboratories, Miami, Florida 33137; College of Pharmacy, University of Florida, Gainesville, Florida 32611. Electronic address: nsbodor@gmail.com.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Bodor
mesh_terms: D001599:Berberine / Q000008:administration & dosage / Q000737:chemistry; D001921:Brain / Q000201:enzymology / Q000378:metabolism*; D003505:Cyclodextrins / Q000737:chemistry*; D016503:Drug Delivery Systems / Q000379:methods*; D004958:Estradiol / Q000008:administration & dosage / Q000737:chemistry; D005079:Excipients / Q000737:chemistry*; D006868:Hydrolysis; D008958:Models, Molecular; D008962:Models, Theoretical; D015394:Molecular Structure; D010084:Oxidation-Reduction; D004364:Pharmaceutical Preparations / Q000008:administration & dosage / Q000737:chemistry; D011220:Pralidoxime Compounds / Q000008:administration & dosage / Q000737:chemistry; D012995:Solubility
chemical_list: D003505:Cyclodextrins; D005079:Excipients; D004364:Pharmaceutical Preparations; D011220:Pralidoxime Compounds; D001599:Berberine; D004958:Estradiol; C028797:pralidoxime
keywords: CNS; blood-brain barrier; complexation; cyclodextrins; drug design; log P; molecular modeling; physicochemical properties; prodrugs