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Mixed Polyethylene Glycol-Modified Breviscapine-Loaded Solid Lipid Nanoparticles for Improved Brain Bioavailability: Preparation, Characterization, and In Vivo Cerebral Microdialysis Evaluation in Adult Sprague Dawley Rats

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Abstract

Breviscapine is used in the treatment of ischemic cerebrovascular diseases, but it has a low bioavailability in the brain due to its poor physicochemical properties and the activity of P-glycoprotein efflux pumps located at the blood–brain barrier. In the present study, breviscapine-loaded solid lipid nanoparticles (SLN) coated with polyethylene glycol (PEG) derivatives were formulated and evaluated for their ability to enhance brain bioavailability. The SLNs were either coated with polyethylene glycol (40) (PEG-40) stearate alone (Bre-GBSLN-PS) or a mixture of PEG-40 stearate and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-PEG2000 (DSPE-PEG2000) (Bre-GBSLN-PS-DSPE) and were characterized both in vitro and in vivo. The mean particle size, polydispersity index, and entrapment efficiency for Bre-GBSLN-PS and Bre-GBSLN-PS-DSPE were 21.60 ± 0.10 and 22.60 ± 0.70 nm, 0.27 ± 0.01 and 0.26 ± 0.04, and 46.89 ± 0.73% and 47.62 ± 1.86%, respectively. The brain pharmacokinetic parameters revealed that the brain bioavailability of breviscapine from the Bre-GBSLN-PS and Bre-GBSLN-PS-DSPE was significantly enhanced (p < 0.01) with the area under concentration–time curve (AUC) of 1.59 ± 0.39 and 1.42 ± 0.58 μg h/mL of breviscapine, respectively, in comparison to 0.11 ± 0.02 μg h/mL from the commercial breviscapine injection. The ratios of the brain AUC for scutellarin in comparison with the plasma scutellarin AUC for commercial breviscapine injection, Bre-GBSLN-PS, and Bre-GBSLN-PS-DSPE were 0.66%, 2.82%, and 4.51%, respectively. These results showed that though both SLN formulations increased brain uptake of breviscapine, Bre-GBSLN-PS-DSPE which was coated with a binary combination of PEG-40 stearate and DSPE-PEG2000 had a better brain bioavailability than Bre-GBSLN-PS. Thus, the coating of SLNs with the appropriate PEG derivative combination could improve brain bioavailability of breviscapine and can be a promising tool for brain drug delivery.

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Acknowledgments

This study was financially supported by the National Natural Science Foundation of China (81001645), Program for New Century Excellent Talents in University (NCET-12-1068), Tianjin Natural Science Foundation (12JCYBJC18700), and the National Key Technology Research and Development Program of China (2012ZX09304007).

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Authors and Affiliations

  1. Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, 88 Yuquan Road, Tianjin, 300193, People’s Republic of China

    Zhidong Liu, Chukwunweike Ikechukwu Okeke, Li Zhang, Hainan Zhao, Jiawei Li, Mike Okweesi Aggrey, Nan Li, Xiujun Guo, Xiaochen Pang, Lili Fan & Lili Guo

  2. Engineering Research Center of Modern Chinese Medicine Discovery and Preparation Technique, Ministry of Education, Tianjin University of Traditional Chinese Medicine, 88 Yuquan Road, Tianjin, 300193, People’s Republic of China

    Zhidong Liu, Chukwunweike Ikechukwu Okeke, Li Zhang, Hainan Zhao, Jiawei Li, Mike Okweesi Aggrey, Nan Li, Xiujun Guo, Xiaochen Pang, Lili Fan & Lili Guo

  3. Department of Experimental Education, Tianjin University of Traditional Chinese Medicine, Tianjin, 300193, People’s Republic of China

    Jiawei Li

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  1. Zhidong Liu
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Correspondence to Zhidong Liu.

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Zhidong Liu and Chukwunweike Ikechukwu Okeke contributed equally to this work.

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Liu, Z., Okeke, C.I., Zhang, L. et al. Mixed Polyethylene Glycol-Modified Breviscapine-Loaded Solid Lipid Nanoparticles for Improved Brain Bioavailability: Preparation, Characterization, and In Vivo Cerebral Microdialysis Evaluation in Adult Sprague Dawley Rats. AAPS PharmSciTech 15, 483–496 (2014). https://doi.org/10.1208/s12249-014-0080-4

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