Journal
BIOMATERIALS
Volume 34, Issue 3, Pages 817-830Publisher
ELSEVIER SCI LTD
DOI: 10.1016/j.biomaterials.2012.10.017
Keywords
Tanshinone IIA; Cationic bovine serum albumin; PEGylated nanoparticles; Cerebral ischemia; Neuroprotection
Funding
- National Natural Science Foundation of China [30902008]
- Youth Scientific Innovation Special Program of Basic research Foundation of Zhejiang University, China [2010QNA7026]
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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.
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