Xu Guangtao, Gu Huan, Hu Bo, Tong Fei, Liu Daojun, Yu Xiaojun, Zheng Yongxia, Gu Jiang
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.
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.
Int J Nanomedicine. 2017 Mar 23;12:2243-2254. doi: 10.2147/IJN.S130842. eCollection 2017.
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)--(poly(ethylenediamine L-glutamate)--poly(L-lysine)) (TNF-α/PEG--(PELG--PLL)) nanoparticles on BI/RI. The particle size of PEG--(PELG--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--(PELG--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--(PELG--PLL) as a potential TNF-α nanocarrier with sustained release significantly enhanced the bioavailability of TNF-α. We propose that the block copolymer PEG--(PELG--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.
脑缺血/再灌注（I/R）损伤（BI/RI）是全球范围内导致死亡和残疾的主要原因。然而，BI/RI的药物治疗效果仍不尽人意。迫切需要创新方法来提高药物敏感性并恢复BI/RI治疗中的神经元活性。本研究的目的是评估负载肿瘤坏死因子（TNF）-α的聚（乙二醇）-（聚（L-谷氨酸乙二胺）-聚（L-赖氨酸））（TNF-α/PEG-（PELG-PLL））纳米颗粒对BI/RI的保护作用。测定了PEG-（PELG-PLL）的粒径以及TNF-α的负载率和释放率。使用大鼠皮质神经元在体外评估纳米颗粒的细胞毒性。对Sprague Dawley大鼠进行游离TNF-α或TNF-α/PEG-（PELG-PLL）复合物预处理，然后进行2小时缺血和22小时再灌注。使用脑水肿比率评估脑水肿，并通过测量脑组织中的超氧化物歧化酶（SOD）活性和丙二醛（MDA）含量来评估抗氧化活性。我们通过测定脑组织中白细胞介素-4（IL-4）、IL-6、IL-8、IL-10和一氧化氮（NO）的水平，以及胶质纤维酸性蛋白（GFAP）、细胞间黏附分子-1（ICAM-1）和半胱天冬酶-3（caspase-3）的表达，进一步评估炎症活性和凋亡水平。我们提供的证据表明，TNF-α预处理减轻了I/R诱导的脑损伤中的氧化应激损伤、炎症活性和凋亡水平，而作为潜在的具有缓释作用的TNF-α纳米载体的嵌段共聚物PEG-（PELG-PLL）的应用显著提高了TNF-α的生物利用度。我们提出，嵌段共聚物PEG-（PELG-PLL）可能作为一种有效的纳米载体增强BI/RI的药物治疗，具有前所未有的临床益处。需要进一步研究以更好地阐明其潜在机制。
