ingest cdrApp 2017-08-15T22:30:54.040Z d91e81c8-5a8a-4e8a-976c-cad4e396e5ee modifyDatastreamByValue RELS-EXT fedoraAdmin 2017-08-15T22:31:47.067Z Setting exclusive relation modifyDatastreamByValue RELS-EXT fedoraAdmin 2017-08-15T22:31:56.220Z Setting exclusive relation addDatastream MD_TECHNICAL fedoraAdmin 2017-08-15T22:31:56.866Z Adding technical metadata derived by FITS modifyDatastreamByValue RELS-EXT fedoraAdmin 2017-08-15T22:32:14.973Z Setting exclusive relation addDatastream MD_FULL_TEXT fedoraAdmin 2017-08-15T22:32:24.563Z Adding full text metadata extracted by Apache Tika modifyDatastreamByValue RELS-EXT fedoraAdmin 2017-08-15T22:32:43.137Z Setting exclusive relation modifyDatastreamByValue RELS-EXT cdrApp 2017-08-22T13:55:18.899Z Setting exclusive relation modifyDatastreamByValue MD_DESCRIPTIVE cdrApp 2018-01-04T17:18:25.135Z modifyDatastreamByValue MD_DESCRIPTIVE cdrApp 2018-01-25T10:16:18.054Z modifyDatastreamByValue MD_DESCRIPTIVE cdrApp 2018-01-27T10:29:37.924Z modifyDatastreamByValue MD_DESCRIPTIVE cdrApp 2018-02-28T21:11:22.768Z modifyDatastreamByValue MD_DESCRIPTIVE cdrApp 2018-03-14T07:18:17.717Z modifyDatastreamByValue MD_DESCRIPTIVE cdrApp 2018-05-17T18:45:26.427Z modifyDatastreamByValue MD_DESCRIPTIVE cdrApp 2018-07-11T05:45:23.513Z modifyDatastreamByValue MD_DESCRIPTIVE cdrApp 2018-07-18T01:59:46.746Z modifyDatastreamByValue MD_DESCRIPTIVE cdrApp 2018-08-16T15:11:13.873Z modifyDatastreamByValue MD_DESCRIPTIVE cdrApp 2018-09-27T01:40:30.457Z modifyDatastreamByValue MD_DESCRIPTIVE cdrApp 2018-10-12T02:12:39.306Z modifyDatastreamByValue MD_DESCRIPTIVE cdrApp 2019-03-20T20:31:06.765Z Dongfen Yuan Author Pharmaceutical Sciences Program Eshelman School of Pharmacy DELIVERY OF THERAPEUTIC PROTEINS TO THE BRAIN 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. Summer 2017 2017 Pharmaceutical sciences Brain delivery, Exosome, Leptin, Pharmacokinetics, Protein conjugate, Protein delivery eng Doctor of Philosophy Dissertation University of North Carolina at Chapel Hill Graduate School Degree granting institution Pharmaceutical Sciences Alexander Kabanov Thesis advisor Shawn Hingtgen Thesis advisor Elena Batrakova Thesis advisor Zhen Gu Thesis advisor William Banks Thesis advisor Alexander Kabanov Kabanov Thesis advisor text Dongfen Yuan Author Pharmaceutical Sciences Program Eshelman School of Pharmacy Delivery of Therapeutic Proteins to the Brain 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. Summer 2017 2017 Pharmaceutical sciences Brain delivery, Exosome, Leptin, Pharmacokinetics, Protein conjugate, Protein delivery eng Doctor of Philosophy Dissertation University of North Carolina at Chapel Hill Graduate School Degree granting institution Pharmaceutical Sciences Alexander Kabanov Thesis advisor Shawn Hingtgen Thesis advisor Elena Batrakova Thesis advisor Zhen Gu Thesis advisor William Banks Thesis advisor Alexander Kabanov Kabanov Thesis advisor text Dongfen Yuan Creator Pharmaceutical Sciences Program Eshelman School of Pharmacy Delivery of Therapeutic Proteins to the Brain 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. Summer 2017 2017 Pharmaceutical sciences Brain delivery, Exosome, Leptin, Pharmacokinetics, Protein conjugate, Protein delivery eng Doctor of Philosophy Dissertation University of North Carolina at Chapel Hill Graduate School Degree granting institution Pharmaceutical Sciences Alexander Kabanov Thesis advisor Shawn Hingtgen Thesis advisor Elena Batrakova Thesis advisor Zhen Gu Thesis advisor William Banks Thesis advisor Alexander Kabanov Kabanov Thesis advisor text Dongfen Yuan Creator Pharmaceutical Sciences Program Eshelman School of Pharmacy Delivery of Therapeutic Proteins to the Brain 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. Summer 2017 2017 Pharmaceutical sciences Brain delivery, Exosome, Leptin, Pharmacokinetics, Protein conjugate, Protein delivery eng Doctor of Philosophy Dissertation University of North Carolina at Chapel Hill Graduate School Degree granting institution Pharmaceutical Sciences Alexander Kabanov Thesis advisor Shawn Hingtgen Thesis advisor Elena Batrakova Thesis advisor Zhen Gu Thesis advisor William Banks Thesis advisor Alexander Kabanov Kabanov Thesis advisor text Dongfen Yuan Creator Division of Pharmacoengineering and Molecular Pharmaceutics Eshelman School of Pharmacy Delivery of Therapeutic Proteins to the Brain 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. Summer 2017 2017 Pharmaceutical sciences Brain delivery, Exosome, Leptin, Pharmacokinetics, Protein conjugate, Protein delivery eng Doctor of Philosophy Dissertation University of North Carolina at Chapel Hill Graduate School Degree granting institution Pharmaceutical Sciences Alexander Kabanov Thesis advisor Shawn Hingtgen Thesis advisor Elena Batrakova Thesis advisor Zhen Gu Thesis advisor William Banks Thesis advisor Alexander Kabanov Kabanov Thesis advisor text Dongfen Yuan Creator Division of Pharmacoengineering and Molecular Pharmaceutics Eshelman School of Pharmacy Delivery of Therapeutic Proteins to the Brain 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. 2017-08 2017 Pharmaceutical sciences Brain delivery, Exosome, Leptin, Pharmacokinetics, Protein conjugate, Protein delivery eng Doctor of Philosophy Dissertation University of North Carolina at Chapel Hill Graduate School Degree granting institution Pharmaceutical Sciences Alexander Kabanov Thesis advisor Shawn Hingtgen Thesis advisor Elena Batrakova Thesis advisor Zhen Gu Thesis advisor William Banks Thesis advisor Alexander Kabanov Kabanov Thesis advisor text Dongfen Yuan Creator Division of Pharmacoengineering and Molecular Pharmaceutics Eshelman School of Pharmacy Delivery of Therapeutic Proteins to the Brain 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. 2017 Pharmaceutical sciences Brain delivery, Exosome, Leptin, Pharmacokinetics, Protein conjugate, Protein delivery eng Doctor of Philosophy Dissertation University of North Carolina at Chapel Hill Graduate School Degree granting institution Pharmaceutical Sciences Alexander Kabanov Thesis advisor Shawn Hingtgen Thesis advisor Elena Batrakova Thesis advisor Zhen Gu Thesis advisor William Banks Thesis advisor Alexander Kabanov Kabanov Thesis advisor text 2017-08 Dongfen Yuan Creator Division of Pharmacoengineering and Molecular Pharmaceutics Eshelman School of Pharmacy Delivery of Therapeutic Proteins to the Brain 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. 2017 Pharmaceutical sciences Brain delivery, Exosome, Leptin, Pharmacokinetics, Protein conjugate, Protein delivery eng Doctor of Philosophy Dissertation University of North Carolina at Chapel Hill Graduate School Degree granting institution Pharmaceutical Sciences Alexander Kabanov Thesis advisor Shawn Hingtgen Thesis advisor Elena Batrakova Thesis advisor Zhen Gu Thesis advisor William Banks Thesis advisor Alexander Kabanov Kabanov Thesis advisor text 2017-08 Dongfen Yuan Creator Division of Pharmacoengineering and Molecular Pharmaceutics Eshelman School of Pharmacy Delivery of Therapeutic Proteins to the Brain 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. 2017 Pharmaceutical sciences Brain delivery, Exosome, Leptin, Pharmacokinetics, Protein conjugate, Protein delivery eng Doctor of Philosophy Dissertation University of North Carolina at Chapel Hill Graduate School Degree granting institution Pharmaceutical Sciences Alexander Kabanov Thesis advisor Shawn Hingtgen Thesis advisor Elena Batrakova Thesis advisor Zhen Gu Thesis advisor William Banks Thesis advisor Alexander Kabanov Kabanov Thesis advisor text 2017-08 Dongfen Yuan Creator Division of Pharmacoengineering and Molecular Pharmaceutics Eshelman School of Pharmacy Delivery of Therapeutic Proteins to the Brain 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. 2017 Pharmaceutical sciences Brain delivery, Exosome, Leptin, Pharmacokinetics, Protein conjugate, Protein delivery eng Doctor of Philosophy Dissertation Pharmaceutical Sciences Alexander Kabanov Thesis advisor Shawn Hingtgen Thesis advisor Elena Batrakova Thesis advisor Zhen Gu Thesis advisor William Banks Thesis advisor Alexander Kabanov Thesis advisor text 2017-08 University of North Carolina at Chapel Hill Degree granting institution Dongfen Yuan Creator Division of Pharmacoengineering and Molecular Pharmaceutics Eshelman School of Pharmacy Delivery of Therapeutic Proteins to the Brain 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. 2017 Pharmaceutical sciences Brain delivery; Exosome; Leptin; Pharmacokinetics; Protein conjugate; Protein delivery eng Doctor of Philosophy Dissertation Pharmaceutical Sciences Alexander Kabanov Thesis advisor Shawn Hingtgen Thesis advisor Elena Batrakova Thesis advisor Zhen Gu Thesis advisor William Banks Thesis advisor Alexander Kabanov Thesis advisor text 2017-08 University of North Carolina at Chapel Hill Degree granting institution Dongfen Yuan Creator Division of Pharmacoengineering and Molecular Pharmaceutics Eshelman School of Pharmacy Delivery of Therapeutic Proteins to the Brain 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. 2017 Pharmaceutical sciences Brain delivery, Exosome, Leptin, Pharmacokinetics, Protein conjugate, Protein delivery eng Doctor of Philosophy Dissertation University of North Carolina at Chapel Hill Graduate School Degree granting institution Pharmaceutical Sciences Alexander Kabanov Thesis advisor Shawn Hingtgen Thesis advisor Elena Batrakova Thesis advisor Zhen Gu Thesis advisor William Banks Thesis advisor Alexander Kabanov Thesis advisor text 2017-08 Dongfen Yuan Creator Division of Pharmacoengineering and Molecular Pharmaceutics Eshelman School of Pharmacy 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. 2017 Pharmaceutical sciences Brain delivery; Exosome; Leptin; Pharmacokinetics; Protein conjugate; Protein delivery eng Doctor of Philosophy Dissertation University of North Carolina at Chapel Hill Graduate School Degree granting institution Alexander Kabanov Thesis advisor Shawn Hingtgen Thesis advisor Elena Batrakova Thesis advisor Zhen Gu Thesis advisor William Banks Thesis advisor Alexander Kabanov Thesis advisor text 2017-08 Yuan_unc_0153D_17230.pdf uuid:58a1e10f-aafb-43ca-89ea-0bb42880dcb1 proquest 2019-08-15T00:00:00 2017-07-22T03:24:00Z application/pdf 10671417 yes