title: Principles of strategic drug delivery to the brain (SDDB): development of anorectic and orexigenic analogs of leptin.
abstract: The blood-brain barrier (BBB) presents a tremendous challenge for the delivery of drugs to the central nervous system (CNS). This includes drugs that target brain receptors for the treatment of obesity and anorexia. Strategic drug delivery to brain (SDDB) is an approach that considers in depth the relations among the BBB, the candidate therapeutic, the CNS target, and the disease state to be treated. Here, we illustrate principles of SDDB with two different approaches to developing drugs based on leptin. In normal body weight humans and in non-obese rodents, leptin is readily transported across the BBB and into the CNS where it inhibits feeding and enhances thermogenesis. However, in obesity, the transport of leptin across the BBB is impaired, resulting in a resistance to leptin. As a result, it is difficult to treat obesity with leptin or its analogs that depend on the leptin transporter for access to the CNS. To treat obesity, we developed a leptin agonist modified by the addition of pluronic block copolymers (P85-leptin). P85-leptin retains biological activity and is capable of crossing the BBB by a mechanism that is not dependent on the leptin transporter. As such, P85-leptin is able to cross the BBB of obese mice at a rate similar to that of native leptin in lean mice. To treat anorexia, we developed a leptin antagonist modified by pegylation (PEG-MLA) that acts primarily by blocking the BBB transporter for endogenous, circulating leptin. This prevents blood-borne, endogenous leptin from entering the CNS, essentially mimicking the leptin resistance seen in obesity, and resulting in a significant increase in adiposity. These examples illustrate two strategies in which an understanding of the interactions among the BBB, CNS targets, and candidate therapeutics under physiologic and diseased conditions can be used to develop drugs effective for the treatment of brain disease.
authors.affiliation: Geriatrics Research Education and Clinical Center - Veterans Affairs Puget Sound Health Care System and Division of Gerontology and Geriatric Medicine, Department of Internal Medicine, University of Washington, Seattle, WA, USA. wabanks1@uw.edu
authors.forename: W A
authors.initials: WA
authors.lastname: Banks
authors.forename: A
authors.initials: A
authors.lastname: Gertler
authors.forename: G
authors.initials: G
authors.lastname: Solomon
authors.forename: L
authors.initials: L
authors.lastname: Niv-Spector
authors.forename: M
authors.initials: M
authors.lastname: Shpilman
authors.forename: X
authors.initials: X
authors.lastname: Yi
authors.forename: E
authors.initials: E
authors.lastname: Batrakova
authors.forename: S
authors.initials: S
authors.lastname: Vinogradov
authors.forename: A V
authors.initials: AV
authors.lastname: Kabanov
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism*; D001921:Brain / Q000378:metabolism; D016503:Drug Delivery Systems / Q000379:methods*; D015195:Drug Design; D020738:Leptin / Q000008:administration & dosage* / Q000031:analogs & derivatives*; D051379:Mice
chemical_list: D020738:Leptin