Delivery of Therapeutic Proteins to the Brain Public Deposited

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  • March 20, 2019
Creator
  • Yuan, Dongfen
    • Affiliation: Eshelman School of Pharmacy, Division of Pharmacoengineering and Molecular Pharmaceutics
Abstract
  • Protein therapeutics have tremendous potentials to treat disorders in central nervous system (CNS). However, delivery of therapeutic dose of proteins to the brain is challenging due to the blood-brain barrier (BBB). In Chapter I, I summarize the current strategies applied to enhance the brain delivery of therapeutic proteins, including strategies to open the BBB, penetrate the BBB, or bypass the BBB. The advantages and challenges for each technology are described. In Chapter II, we explore strategies to improve the brain delivery of leptin for treatment of obesity. Leptin is an adipocyte-secreted hormone that is delivered via a saturable transporter system across the BBB to the brain where it acts on receptors in hypothalamus to control appetite and thermogenesis. Peripheral resistance to leptin due to its impaired brain delivery prevents therapeutic use of leptin in overweight and moderately obese patients. To address this problem, we modify the N-terminal amine of leptin with Pluronic P85 (LepNP85) and administer this conjugate intranasally using the nose-to-brain route to bypass the BBB. We compare this conjugate with the native leptin, the N-terminal leptin conjugate with poly(ethylene glycol) (LepNPEG5K), and two conjugates of leptin with Pluronic P85 attached randomly to the lysine amino groups of the hormone. Our work suggests that selective modification at the N-terminal preserves leptin activity and modification with P85 enhances the nose-to-brain transport of leptin. In conclusion, LepNP85 with optimized conjugation chemistry is a promising candidate for treatment of obesity. In Chapter III, we demonstrate for the first time that naïve macrophage exosomes interact with intercellular adhesion molecule 1 (ICAM-1) and C-type lectin receptors on brain endothelial cells that form BBB. Upregulation of ICAM-1, a common process in inflammation, promotes macrophage exosomes uptake in the BBB cells. We further demonstrate in vivo that naïve macrophage exosomes, after intravenous (IV) administration, cross the BBB and deliver a cargo protein to the brain parenchyma. The delivery is enhanced in the presence of brain inflammation. Taken together, macrophage exosomes are promising nanocarriers for brain delivery of therapeutic proteins.
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Rights statement
  • In Copyright
Advisor
  • Batrakova, Elena
  • Banks, William
  • Kabanov, Alexander
  • Hingtgen, Shawn
  • Gu, Zhen
Degree
  • Doctor of Philosophy
Degree granting institution
  • University of North Carolina at Chapel Hill Graduate School
Graduation year
  • 2017
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