title: Protective effects of cationic bovine serum albumin-conjugated PEGylated tanshinone IIA nanoparticles on cerebral ischemia.
abstract: 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-α, IL-1β and IL-6. Furthermore, CBSA-PEG-TIIA-NPs significantly decreased the mRNA expressions of iNOS and p38MAPK, upregulated PPARγ 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.
authors.affiliation: College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China. xinliu98@126.com
authors.forename: Xin
authors.initials: X
authors.lastname: Liu
authors.forename: Chiying
authors.initials: C
authors.lastname: An
authors.forename: Peng
authors.initials: P
authors.lastname: Jin
authors.forename: Xuesong
authors.initials: X
authors.lastname: Liu
authors.forename: Longhu
authors.initials: L
authors.lastname: Wang
mesh_terms: D045784:Abietanes / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D002545:Brain Ischemia / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D002417:Cattle; D004337:Drug Carriers / Q000737:chemistry*; D005786:Gene Expression Regulation / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D053583:Interleukin-1beta / Q000276:immunology; D015850:Interleukin-6 / Q000276:immunology; D053758:Nanoparticles / Q000737:chemistry* / Q000648:ultrastructure; D047495:PPAR gamma / Q000235:genetics; D011092:Polyethylene Glycols / Q000737:chemistry; D051381:Rats; D017207:Rats, Sprague-Dawley; D012710:Serum Albumin, Bovine / Q000737:chemistry; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics
chemical_list: D045784:Abietanes; D004337:Drug Carriers; D007166:Immunosuppressive Agents; D053583:Interleukin-1beta; D015850:Interleukin-6; D047495:PPAR gamma; D014409:Tumor Necrosis Factor-alpha; C021751:tanshinone; D012710:Serum Albumin, Bovine; D011092:Polyethylene Glycols; D048051:p38 Mitogen-Activated Protein Kinases