Theranostics 2019; 9(23):6991-7002. doi:10.7150/thno.35791 This issue Cite

Research Paper

Anti-edema and antioxidant combination therapy for ischemic stroke via glyburide-loaded betulinic acid nanoparticles

Gang Deng1,2*, Chao Ma1,3*, Haitian Zhao1,4*, Shenqi Zhang1,2*, Jun Liu1, Fuyao Liu1, Zeming Chen1, Ann T. Chen5, Xin Yang1,4, Jonathan Avery1, Pan Zou1, Fengyi Du1, Keun-poong Lim6, Daniel Holden6, Songye Li6, Richard E. Carson5,6, Yiyun Huang5, Qianxue Chen2, W. Taylor Kimberly7, J. Marc Simard8, Kevin N. Sheth9✉, Jiangbing Zhou1,5✉

1. Department of Neurosurgery, Yale University, New Haven, CT, 06510, USA.
2. Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan 430060, China.
3. College of Biological Sciences and Biotechnology, Beijing Forestry University, Beijing 100083, China.
4. School of Chemistry and Chemical Engineering, Harbin Institute of Technology, Harbin 150090, China.
5. Department of Biomedical Engineering, Yale University, New Haven, CT, 06510, USA
6. PET Center, Department of Radiology and Biomedical Imaging, Yale University, New Haven, CT, 06510, USA
7. Department of Neurology, Division of Neurocritical Care, Massachusetts General Hospital, Boston, MA, 02114, USA.
8. Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, MD, 21201, USA.
9. Department of Neurology, Yale University, New Haven, CT, 06510, USA.
*These authors contributed equally.

Citation:
Deng G, Ma C, Zhao H, Zhang S, Liu J, Liu F, Chen Z, Chen AT, Yang X, Avery J, Zou P, Du F, Lim Kp, Holden D, Li S, Carson RE, Huang Y, Chen Q, Kimberly WT, Simard JM, Sheth KN, Zhou J. Anti-edema and antioxidant combination therapy for ischemic stroke via glyburide-loaded betulinic acid nanoparticles. Theranostics 2019; 9(23):6991-7002. doi:10.7150/thno.35791. https://www.thno.org/v09p6991.htm
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Abstract

Graphic abstract

Stroke is a deadly disease without effective pharmacotherapies, which is due to two major reasons. First, most therapeutics cannot efficiently penetrate the brain. Second, single agent pharmacotherapy may be insufficient and effective treatment of stroke requires targeting multiple complementary targets. Here, we set to develop single component, multifunctional nanoparticles (NPs) for targeted delivery of glyburide to the brain for stroke treatment.

Methods: To characterize the brain penetrability, we radiolabeled glyburide, intravenously administered it to stroke- bearing mice, and determined its accumulation in the brain using positron emission tomography-computed tomography (PET/CT). To identify functional nanomaterials to improve drug delivery to the brain, we developed a chemical extraction approach and tested it for isolation of nanomaterials from E. ulmoides, a medicinal herb. To assess the therapeutic benefits, we synthesized glyburide-loaded NPs and evaluated them in stroke- bearing mice.

Results: We found that glyburide has a limited ability to penetrate the ischemic brain. We identified betulinic acid (BA) capable of forming NPs, which, after intravenous administration, efficiently penetrate the brain and significantly reduce ischemia-induced infarction as an antioxidant agent. We demonstrated that BA NPs enhance delivery of glyburide, leading to therapeutic benefits significantly greater than those achieved by either glyburide or BA NPs.

Conclusion: This study suggests a new direction to identify functional nanomaterials and a simple approach to achieving anti-edema and antioxidant combination therapy. The resulting glyburide- loaded BA NPs may be translated into clinical applications to improve clinical management of stroke.

Keywords: ischemic stroke, betulinic acid, glyburide, antioxidant, combination therapy


Citation styles

APA
Deng, G., Ma, C., Zhao, H., Zhang, S., Liu, J., Liu, F., Chen, Z., Chen, A.T., Yang, X., Avery, J., Zou, P., Du, F., Lim, K.p., Holden, D., Li, S., Carson, R.E., Huang, Y., Chen, Q., Kimberly, W.T., Simard, J.M., Sheth, K.N., Zhou, J. (2019). Anti-edema and antioxidant combination therapy for ischemic stroke via glyburide-loaded betulinic acid nanoparticles. Theranostics, 9(23), 6991-7002. https://doi.org/10.7150/thno.35791.

ACS
Deng, G.; Ma, C.; Zhao, H.; Zhang, S.; Liu, J.; Liu, F.; Chen, Z.; Chen, A.T.; Yang, X.; Avery, J.; Zou, P.; Du, F.; Lim, K.p.; Holden, D.; Li, S.; Carson, R.E.; Huang, Y.; Chen, Q.; Kimberly, W.T.; Simard, J.M.; Sheth, K.N.; Zhou, J. Anti-edema and antioxidant combination therapy for ischemic stroke via glyburide-loaded betulinic acid nanoparticles. Theranostics 2019, 9 (23), 6991-7002. DOI: 10.7150/thno.35791.

NLM
Deng G, Ma C, Zhao H, Zhang S, Liu J, Liu F, Chen Z, Chen AT, Yang X, Avery J, Zou P, Du F, Lim Kp, Holden D, Li S, Carson RE, Huang Y, Chen Q, Kimberly WT, Simard JM, Sheth KN, Zhou J. Anti-edema and antioxidant combination therapy for ischemic stroke via glyburide-loaded betulinic acid nanoparticles. Theranostics 2019; 9(23):6991-7002. doi:10.7150/thno.35791. https://www.thno.org/v09p6991.htm

CSE
Deng G, Ma C, Zhao H, Zhang S, Liu J, Liu F, Chen Z, Chen AT, Yang X, Avery J, Zou P, Du F, Lim Kp, Holden D, Li S, Carson RE, Huang Y, Chen Q, Kimberly WT, Simard JM, Sheth KN, Zhou J. 2019. Anti-edema and antioxidant combination therapy for ischemic stroke via glyburide-loaded betulinic acid nanoparticles. Theranostics. 9(23):6991-7002.

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