Protective effects of cationic bovine serum albumin-conjugated PEGylated tanshinone IIA nanoparticles on cerebral ischemia
Protective effects of cationic bovine serum albumin-conjugated PEGylated tanshinone IIA nanoparticles on cerebral ischemia
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阳离子牛血清白蛋白聚乙二醇化丹参酮IIA纳米粒对脑缺血的保护作用
DOI：
10.1016/j.biomaterials.2012.10.017
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发表时间：
2013-01-01
期刊：
影响因子：
14
通讯作者：
Wang, Longhu
中科院分区：
文献类型：
--
作者：
Liu, Xin;An, Chiying;Wang, Longhu
丹参酮IIA是治疗脑缺血的良好药物，但其半衰期短、血脑屏障通透性差限制了其疗效。在本研究中，我们成功地开发了阳离子牛血清白蛋白结合丹参酮IIA聚乙二醇化纳米粒（CBSA-PEG-TIIA-NPs）。建立大鼠脑缺血模型，评价CBSA-PEG-TIIA-NPs的治疗效果和保护机制。CBSA-PEG-TIIA-NP显示平均粒径为118 +/-14 nm，载药率和包封率分别为5.69 +/-0.6%和83.2 +/-2.6%。药代动力学研究表明，CBSA-PEG-TIIA-NPs能显著延长TIIA溶液的循环时间，提高血药浓度。生物分布和脑摄取研究证实CBSA-PEG-TIIA-NP具有更好的脑递送功效，在脑中具有高蓄积。CBSA-PEG-TIIA-NPs可明显改善脑梗死体积、神经功能缺损程度和组织病理学严重程度。用CBSA-PEG-TIIA-NP处理显著抑制了MPO、TNF-α、IL-1 β p和IL-6的水平。CBSA-PEG-TIIA-NPs可显著降低iNOS和p38 MAPK的mRNA表达，上调PPAR γ的表达，抑制iNOS、GFAP和p38 MAPK的磷酸化。这些结果表明CBSA-PEG-TIIA-NPs通过调节脑缺血中的炎症级联反应和神经元信号通路对缺血性卒中具有显著的神经保护作用。皇冠版权所有（c）2012由爱思唯尔有限公司出版。保留所有权利。
Tanshinone IIA is a good candidate for treating cerebral ischemia, but its short half-life and poor permeability across the blood brain-barrier (BBB) limit its curative efficacy. In this study, we successfully developed cationic bovine serum albumin-conjugated tanshinone IIA PEGylated nanoparticles (CBSA-PEG-TIIA-NPs). A cerebral ischemia rat model was established to evaluate the treatment efficacy and protective mechanism of CBSA-PEG-TIIA-NPs. CBSA-PEG-TIIA-NPs showed the mean particle size 118 +/- 14 nm with drug loaded ratio and encapsulation efficiency 5.69 +/- 0.6% and 83.2 +/- 2.6%, respectively. The pharmacokinetics demonstrated that CBSA-PEG-TIIA-NPs could significantly prolong circulation time and increase plasma concentration compared with intravenously administrated TIIA solution. The biodistribution and brain uptake study confirmed that CBSA-PEG-TIIA-NPs possessed better brain delivery efficacy with a high accumulation in brain. CBSA-PEG-TIIA-NPs obviously ameliorated infarct volume, neurological deficit and histopathological severity. Treatment with CBSA-PEG-TIIA-NPs markedly inhibited the levels of the MPO, TNF-alpha, IL-1 beta p and IL-6. Furthermore, CBSA-PEG-TIIA-NPs significantly decreased the mRNA expressions of iNOS and p38MAPK, upregulated PPAR gamma expression, and inhibited the protein levels of iNOS, GFAP and p38MAPK phosphorylation. These results demonstrated that CBSA-PEG-TIIA-NPs possessed remarkable neuroprotective effects on ischemic stroke through modulation of inflammatory cascades and neuronal signal pathways involved in cerebral ischemia. Crown Copyright (c) 2012 Published by Elsevier Ltd. All rights reserved.