title: PEG-b-(PELG-g-PLL) nanoparticles as TNF-α nanocarriers: potential cerebral ischemia/reperfusion injury therapeutic applications.
abstract: Brain ischemia/reperfusion (I/R) injury (BI/RI) is a leading cause of death and disability worldwide. However, the outcome of pharmacotherapy for BI/RI remains unsatisfactory. Innovative approaches for enhancing drug sensitivity and recovering neuronal activity in BI/RI treatment are urgently needed. The purpose of this study was to evaluate the protective effects of tumor necrosis factor (TNF)-α-loaded poly(ethylene glycol)-b-(poly(ethylenediamine L-glutamate)-g-poly(L-lysine)) (TNF-α/PEG-b-(PELG-g-PLL)) nanoparticles on BI/RI. The particle size of PEG-b-(PELG-g-PLL) and the loading and release rates of TNF-α were determined. The nanoparticle cytotoxicity was evaluated in vitro using rat cortical neurons. Sprague Dawley rats were preconditioned with free TNF-α or TNF-α/PEG-b-(PELG-g-PLL) polyplexes and then subjected to 2 hours ischemia and 22 hours reperfusion. Brain edema was assessed using the brain edema ratio, and the antioxidative activity was assessed by measuring the superoxide dismutase (SOD) activity and the malondialdehyde (MDA) content in the brain tissue. We further estimated the inflammatory activity and apoptosis level by determining the levels of interleukin-4 (IL-4), IL-6, IL-8, IL-10, and nitric oxide (NO), as well as the expression of glial fibrillary acidic protein (GFAP), intercellular adhesion molecule-1 (ICAM-1), and cysteine aspartase-3 (caspase-3), in the brain tissue. We provide evidence that TNF-α preconditioning attenuated the oxidative stress injury, the inflammatory activity, and the apoptosis level in I/R-induced cerebral injury, while the application of block copolymer PEG-b-(PELG-g-PLL) as a potential TNF-α nanocarrier with sustained release significantly enhanced the bioavailability of TNF-α. We propose that the block copolymer PEG-b-(PELG-g-PLL) may function as a potent nanocarrier for augmenting BI/RI pharmacotherapy, with unprecedented clinical benefits. Further studies are needed to better clarify the underlying mechanisms.
authors.affiliation: Department of Pathology and Chemistry, Provincial Key Laboratory of Infectious Diseases and Immunopathology, Collaborative and Creative Center, Molecular Diagnosis and Personalized Medicine, Shantou University Medical College, Shantou, Guangdong; Department of Pathology, Provincial Key Discipline of Pharmacology, Jiaxing University Medical College, Jiaxing, Zhejiang, People's Republic of China.
authors.forename: Guangtao
authors.initials: G
authors.lastname: Xu
authors.affiliation: Department of Pathology and Chemistry, Provincial Key Laboratory of Infectious Diseases and Immunopathology, Collaborative and Creative Center, Molecular Diagnosis and Personalized Medicine, Shantou University Medical College, Shantou, Guangdong; Department of Physics, University of Maryland, College Park, Annapolis, MD, USA.
authors.forename: Huan
authors.initials: H
authors.lastname: Gu
authors.affiliation: Department of Chemical Pathology, Jiaxing Hospital of Traditional Chinese Medicine, Zhejiang Chinese Medical University, Jiaxing, Zhejiang, People's Republic of China.
authors.forename: Bo
authors.initials: B
authors.lastname: Hu
authors.affiliation: Department of Pathology, Provincial Key Discipline of Pharmacology, Jiaxing University Medical College, Jiaxing, Zhejiang, People's Republic of China.
authors.forename: Fei
authors.initials: F
authors.lastname: Tong
authors.affiliation: Department of Pathology and Chemistry, Provincial Key Laboratory of Infectious Diseases and Immunopathology, Collaborative and Creative Center, Molecular Diagnosis and Personalized Medicine, Shantou University Medical College, Shantou, Guangdong.
authors.forename: Daojun
authors.initials: D
authors.lastname: Liu
authors.affiliation: Department of Pathology and Chemistry, Provincial Key Laboratory of Infectious Diseases and Immunopathology, Collaborative and Creative Center, Molecular Diagnosis and Personalized Medicine, Shantou University Medical College, Shantou, Guangdong.
authors.forename: Xiaojun
authors.initials: X
authors.lastname: Yu
authors.affiliation: Department of Pathology and Chemistry, Provincial Key Laboratory of Infectious Diseases and Immunopathology, Collaborative and Creative Center, Molecular Diagnosis and Personalized Medicine, Shantou University Medical College, Shantou, Guangdong; Department of Pathology, Provincial Key Discipline of Pharmacology, Jiaxing University Medical College, Jiaxing, Zhejiang, People's Republic of China.
authors.forename: Yongxia
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: Department of Pathology and Chemistry, Provincial Key Laboratory of Infectious Diseases and Immunopathology, Collaborative and Creative Center, Molecular Diagnosis and Personalized Medicine, Shantou University Medical College, Shantou, Guangdong.
authors.forename: Jiang
authors.initials: J
authors.lastname: Gu
mesh_terms: D000818:Animals; D001929:Brain Edema / Q000150:complications / Q000188:drug therapy / Q000473:pathology; D002545:Brain Ischemia / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D053148:Caspase 3 / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D004337:Drug Carriers / Q000737:chemistry*; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D008970:Molecular Weight; D053758:Nanoparticles / Q000737:chemistry*; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D010316:Particle Size; D011092:Polyethylene Glycols / Q000138:chemical synthesis / Q000737:chemistry*; D011107:Polylysine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D013482:Superoxide Dismutase / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D004337:Drug Carriers; D005904:Glial Fibrillary Acidic Protein; D014409:Tumor Necrosis Factor-alpha; C000619449:poly(ethylene glycol)-b-(poly(ethylenediamine glutamate)-g-poly(lysine)); C443714:polylysine-graft-(poly(ethylene glycol)); D018799:Intercellular Adhesion Molecule-1; D011107:Polylysine; D011092:Polyethylene Glycols; D008315:Malondialdehyde; D013482:Superoxide Dismutase; D053148:Caspase 3
keywords: PEG-b-(PELG-g-PLL); TNF-α; brain; ischemia/reperfusion