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Human Serum Albumin-enriched Clopidogrel Bisulfate Nanoparticle Alleviates Cerebral Ischemia–Reperfusion Injury in Rats

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Abstract

Purpose

Cerebral ischemia–reperfusion (I/R) injury remains a leading cause of mobility and mortality among patients with ischemic stroke. This study aims to develop a human serum albumin (HSA)-enriched nanoparticle platform for solubilizing clopidogrel bisulfate (CLP) for intravenous administration, and to explore the protective effect of HSA-enriched nanoparticles loaded with CLP (CLP-ANPs) against cerebral I/R injury in transient middle cerebral artery occlusion (MCAO) rat model.

Methods

CLP-ANPs were synthesized via a modified nanoparticle albumin-bound technology, lyophilized, and then characterized by morphology, particle size, zeta potential, drug loading capacity, encapsulation efficiency, stability and in vitro release kinetics. In vivo pharmacokinetic studies were conducted using Sprague–Dawley (SD) rats. Also, an MCAO rat model was established to explore the therapeutic effect of CLP-ANPs on cerebral I/R injury.

Results

CLP-ANPs remained spherical particles with a layer of proteins forming protein corona. Lyophilized CLP-ANPs after dispersion displayed an average size of about 235.6 ± 6.6 nm (PDI = 0.16 ± 0.08) with a zeta potential of about − 13.5 ± 1.8 mV. CLP-ANPs achieved sustained release for up to 168 h in vitro. Next, a single injection of CLP-ANPs dose-dependently reversed the histopathological changes induced by cerebral I/R injury possibly via attenuating apoptosis and reducing oxidative damages in the brain tissues.

Conclusions

CLP-ANPs represent a promising and translatable platform system for the management of cerebral I/R injury during ischemic stroke.

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Data Availability

The authors declare that the data supporting the findings of this study are available within the paper and its Supplementary Information files. Should any raw data files be needed in another format they are available from the corresponding author upon reasonable request.

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Acknowledgements

L Deng and YT Luo designed the project. YT Luo performed all experiments and drafted the manuscript. YL Xia and HN Zhang helped with animal studies. YZ Lin, LL He, T Gong, and ZR Zhang: resources and discussions. L Deng, conceptualization, resources, project administration, writing—review & editing.

Funding

Authors are grateful for the financial support from the Natural Science Foundation of China (U20A20411), Sichuan Province Department of Science and Technology (2021YJ0224), 111 project (B18035) and the Fundamental Research Funds for the Central Universities.

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Authors and Affiliations

  1. Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, 610041, China

    Yiting Luo, Yunli Xia, Haonan Zhang, Yunzhu Lin, Tao Gong, Zhirong Zhang & Li Deng

  2. College of Pharmacy, Southwest Minzu University, Chengdu, 610041, China

    Yiting Luo & Lili He

  3. Department of Pharmacy, Evidence-Based Pharmacy Center, West China Second University Hospital, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Sichuan University, Chengdu, 610041, China

    Yunzhu Lin

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  1. Yiting Luo
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Correspondence to Li Deng.

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Luo, Y., Xia, Y., Zhang, H. et al. Human Serum Albumin-enriched Clopidogrel Bisulfate Nanoparticle Alleviates Cerebral Ischemia–Reperfusion Injury in Rats. Pharm Res 40, 1821–1833 (2023). https://doi.org/10.1007/s11095-023-03543-8

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