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

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.

• Authors: Gang Deng, Chao Ma, Haitian Zhao, Shenqi Zhang, Jun Liu, Fuyao Liu, Zeming Chen, Ann T Chen, Xin Yang, Jonathan Avery, Pan Zou, Fengyi Du, Keun-Poong Lim, Daniel Holden, Songye Li, Richard E Carson, Yiyun Huang, Qianxue Chen, W Taylor Kimberly, J Marc Simard, Kevin N Sheth, Jiangbing Zhou
• Journal: Theranostics (Theranostics) Vol. 9 Issue 23 Pg. 6991-7002 ( 2019) ISSN: 1838-7640 [Electronic] Australia
• PMID: 31660082 (Publication Type: Evaluation Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © The author(s).

Chemical References

• Antioxidants
• Drugs, Chinese Herbal
• Pentacyclic Triterpenes
• Triterpenes
• Glyburide
• Betulinic Acid

Topics

• Animals
• Antioxidants (administration & dosage, chemistry)
• Brain Edema (diagnostic imaging, drug therapy)
• Drug Delivery Systems (instrumentation, methods)
• Drug Therapy, Combination
• Drugs, Chinese Herbal (administration & dosage, chemistry)
• Eucommiaceae (chemistry)
• Glyburide (administration & dosage, chemistry)
• Humans
• Male
• Mice
• Mice, Inbred C57BL
• Nanoparticles (chemistry)
• Pentacyclic Triterpenes
• Positron Emission Tomography Computed Tomography
• Rats
• Rats, Sprague-Dawley
• Stroke (diagnostic imaging, drug therapy)
• Triterpenes (administration & dosage, chemistry)
• Betulinic Acid