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Adventitial injection of HA/SA hydrogel loaded with PLGA rapamycin nanoparticle inhibits neointimal hyperplasia in a rat aortic wire injury model

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Abstract

Neointimal hyperplasia is a persistent complication after vascular interventions, and it is also the leading cause of vascular graft restenosis and failure after arterial interventions, so novel treatment methods are needed to treat this complication. We hypothesized that adventitial injection of HA/SA hydrogel loaded with PLGA rapamycin nanoparticle (hydrogel-PLGA-rapamycin) could inhibit neointimal hyperplasia in a rat aortic wire injury model. The HA/SA hydrogel was fabricated by the interaction of hyaluronic acid (HA), sodium alginate (SA), and CaCO3; and loaded with PLGA rapamycin nanoparticle or rhodamine uniformly. A SD rat aortic wire injury induced neointimal hyperplasia model was developed, the control group only received wire injury, the adventitial application group received 10 μL hydrogel-PLGA-rapamycin after wire injury, and the adventitial injection group received 10 μL hydrogel-PLGA-rapamycin injected into the aortic adventitia after wire injury. Tissues were harvested at day 21 and analyzed by histology and immunohistochemical staining. Hydrogel loaded with rhodamine can be successfully injected into the aortic adventitia and was encapsuled by the adventitia. The hydrogel could be seen beneath the adventitia after adventitial injection but was almost degraded at day 21. There was a significantly thinner neointima in the adventitial application group and adventitial injection group compared to the control group (p = 0.0009). There were also significantly fewer CD68+ (macrophages) cells (p = 0.0012), CD3+ (lymphocytes) cells (p = 0.0011), p-mTOR+ cells (p = 0.0019), PCNA+ cells (p = 0.0028) in the adventitial application and adventitial injection groups compared to the control group. The endothelial cells expressed arterial identity markers (Ephrin-B2 and dll-4) in all these three groups. Adventitial injection of hydrogel-PLGA-rapamycin can effectively inhibit neointimal hyperplasia after rat aortic wire injury. This may be a promising drug delivery method and therapeutic choice to inhibit neointimal hyperplasia after vascular interventions.

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Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

Abbreviations

DAB:

3,3 N-diaminobenzidine tetrahydrochloride

H&E:

Hematoxylin and eosin

HRP:

Horseradish peroxidase

SD:

Sprague Dawley

TGF:

Transforming growth factor

PLGA:

Polylactic-co-glycolic acid

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Funding

This study was funded by the National Natural Science Foundation of China to Hualong Bai (Grant No: 81870369) and Key Projects of Medical Science and Technology in Henan Province (Grant No: SBGJ202002035).

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Authors and Affiliations

  1. Department of Vascular and Endovascular Surgery, First Affiliated Hospital of Zhengzhou University, Henan, China

    Hualong Bai

  2. Department of Physiology, Medical School of Zhengzhou University, Henan, China

    Hualong Bai & Wang Wang

  3. Key Vascular Physiology and Applied Research Laboratory of Zhengzhou City, Henan, China

    Hualong Bai, Haoliang Wu, Liwei Zhang, Peng Sun, Yuanfeng Liu, Boao Xie, Cong Zhang & Shunbo Wei

  4. School of Material Science and Engineering & Henan Key Laboratory of Advanced Magnesium Alloy & Key Laboratory of Materials Processing and Mold Technology (Ministry of Education), Zhengzhou University, Henan, China

    Jiangan Li

Authors
  1. Hualong Bai
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  2. Haoliang Wu
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  3. Liwei Zhang
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  4. Peng Sun
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  7. Cong Zhang
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  9. Wang Wang
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Contributions

HB and HW designed the experiments, performed data analysis, and wrote and revised the manuscript. LZ, PS, BX, and SW conducted animal studies, histology experiments, and compiled data. YL, CZ, WW and JL compiled the data. HB obtained funding.

Corresponding author

Correspondence to Hualong Bai.

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Ethics approval and consent to participate

This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of the First Affiliated Hospital of Zhengzhou University.

Competing interest

The authors declare no competing interests.

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Bai, H., Wu, H., Zhang, L. et al. Adventitial injection of HA/SA hydrogel loaded with PLGA rapamycin nanoparticle inhibits neointimal hyperplasia in a rat aortic wire injury model. Drug Deliv. and Transl. Res. 12, 2950–2959 (2022). https://doi.org/10.1007/s13346-022-01158-x

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