Intranasal delivery of N-terminal modified leptin-pluronic conjugate for treatment of obesity.
Leptin is an adipocyte-secreted hormone that is delivered via a specific transport system across the blood-brain barrier (BBB) to the brain where it acts on the hypothalamus receptors 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 modified the N-terminal amine of leptin with Pluronic P85 (LepNP85) and administered this conjugate intranasally using the nose-to-brain (INB) route to bypass the BBB. We compared 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. Compared to the random conjugates of leptin with P85, LepNP85 has shown higher affinity upon binding with the leptin receptor, and similarly to native hormone activated hypothalamus receptors after direct injection into brain. After INB delivery, LepNP85 conjugate was transported to the brain and accumulated in the hypothalamus and hippocampus to a greater extent than the native leptin and LepNPEG5K and activated leptin receptors in hypothalamus at lower dose than native leptin. Our work suggests that LepNP85 can access the brain directly after INB delivery and confirms our hypothesis that the improvement in brain accumulation of this conjugate is due to its enhanced brain absorption. In conclusion, the LepNP85 with optimized conjugation chemistry is a promising candidate for treatment of obesity.
Center for Nanotechnology in Drug Delivery, Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, NC 27599, USA.
Dongfen
D
Yuan
Center for Nanotechnology in Drug Delivery, Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, NC 27599, USA.
Xiang
X
Yi
Center for Nanotechnology in Drug Delivery, Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, NC 27599, USA.
Yuling
Y
Zhao
Research Computer Center, University of North Carolina at Chapel Hill, NC 27599, USA.
Chi-Duen
CD
Poon
Research and Development, Veterans Affairs Puget Sound Health Care System, Seattle, WA, USA.
Kristin M
KM
Bullock
Geriatric Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA 98108, USA; Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington School of Medicine, Seattle, WA 98104, USA.
Kim M
KM
Hansen
Geriatric Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA 98108, USA; Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington School of Medicine, Seattle, WA 98104, USA.
Therese S
TS
Salameh
Research and Development, VA Medical Center and Division of Geriatrics, School of Medicine, St. Louis University, St. Louis, MO 63110, USA.
Susan A
SA
Farr
Geriatric Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA 98108, USA; Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington School of Medicine, Seattle, WA 98104, USA.
William A
WA
Banks
Center for Nanotechnology in Drug Delivery, Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, NC 27599, USA; Laboratory of Chemical Design of Bionanomaterials, Faculty of Chemistry, M.V. Lomonosov Moscow State University, Moscow 119992, Russia. Electronic address: kabanov@email.unc.edu.
Alexander V
AV
Kabanov
D000281:Administration, Intranasal; D000818:Animals; D001921:Brain / Q000378:metabolism*; D020738:Leptin / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D008297:Male; D051379:Mice; D009765:Obesity / Q000188:drug therapy; D011060:Poloxalene / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D054411:Receptors, Leptin / Q000378:metabolism
D020738:Leptin; D054411:Receptors, Leptin; C422648:pluronic block copolymer p85; D011060:Poloxalene
Leptin; Nose-to-brain delivery; Obesity; Pharmacokinetics; Pluronic block copolymer; Protein-polymer conjugation