title: Agile delivery of protein therapeutics to CNS.
abstract: A variety of therapeutic proteins have shown potential to treat central nervous system (CNS) disorders. Challenge to deliver these protein molecules to the brain is well known. Proteins administered through parenteral routes are often excluded from the brain because of their poor bioavailability and the existence of the blood-brain barrier (BBB). Barriers also exist to proteins administered through non-parenteral routes that bypass the BBB. Several strategies have shown promise in delivering proteins to the brain. This review, first, describes the physiology and pathology of the BBB that underscore the rationale and needs of each strategy to be applied. Second, major classes of protein therapeutics along with some key factors that affect their delivery outcomes are presented. Third, different routes of protein administration (parenteral, central intracerebroventricular and intraparenchymal, intranasal and intrathecal) are discussed along with key barriers to CNS delivery associated with each route. Finally, current delivery strategies involving chemical modification of proteins and use of particle-based carriers are overviewed using examples from literature and our own work. Whereas most of these studies are in the early stage, some provide proof of mechanism of increased protein delivery to the brain in relevant models of CNS diseases, while in few cases proof of concept had been attained in clinical studies. This review will be useful to broad audience of students, academicians and industry professionals who consider critical issues of protein delivery to the brain and aim developing and studying effective brain delivery systems for protein therapeutics.
authors: Division of Molecular Pharmaceutics and Center for Nanotechnology in Drug Delivery, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. Electronic address: xiang_yi@unc.edu.
authors: Xiang
authors: X
authors: Yi
authors: Division of Molecular Pharmaceutics and Center for Nanotechnology in Drug Delivery, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors: Devika S
authors: DS
authors: Manickam
authors: Department of Pharmaceutical Sciences and Center for Drug Delivery and Nanomedicine, University of Nebraska Medical Center, Omaha, NE 68198, USA.
authors: Anna
authors: A
authors: Brynskikh
authors: Division of Molecular Pharmaceutics and Center for Nanotechnology in Drug Delivery, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Faculty of Chemistry, M.V. Lomonosov Moscow State University, 119899 Moscow, Russia. Electronic address: akabanov@email.unc.edu.
authors: Alexander V
authors: AV
authors: Kabanov
mesh_terms: D001812:Blood-Brain Barrier / Q000473:pathology / Q000502:physiology*; D002493:Central Nervous System Diseases / Q000188:drug therapy*; D004337:Drug Carriers; D006801:Humans; D053758:Nanoparticles; D010455:Peptides / Q000627:therapeutic use*; D011506:Proteins / Q000627:therapeutic use*
chemical_list: D004337:Drug Carriers; D010455:Peptides; D011506:Proteins
keywords: Administration route; Blood–brain barrier; Brain delivery; Central nervous system; Protein delivery; Protein therapeutics