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  3. A bioinspired hyperthermic macrophage-based polypyrrole-polyethylenimine (Ppy-PEI) nanocomplex carrier to prevent and disrupt thrombotic fibrin clots

A bioinspired hyperthermic macrophage-based polypyrrole-polyethylenimine (Ppy-PEI) nanocomplex carrier to prevent and disrupt thrombotic fibrin clots

  • Acta Biomater. 2019 Sep 15;96:468-479. doi: 10.1016/j.actbio.2019.06.053.
Thierry Burnouf 1,  Chih-Hwa Chen 2,  Shun-Jen Tan 3,  Ching-Li Tseng 1,  Kun-Ying Lu 4,  Lee-Hsin Chang 5,  Batzaya Nyambat 1,  Shao-Chan Huang 1,  Pei-Ru Jheng 1,  Robby Nur Aditya 1,  Fwu-Long Mi 6,  Er-Yuan Chuang 7
Affiliations

Affiliations

  • 1 Graduate Institute of Biomedical Materials and Tissue Engineering, and International PhD Program in Biomedical Engineering, College of Biomedical Engineering, Taipei Medical University, Taipei, Taiwan, ROC.
  • 2 Department of Orthopedics, Shuang Ho Hospital, Taipei Medical University, Taipei, Taiwan, ROC; School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan, ROC; School of Biomedical Engineering, College of Biomedical Engineering, Taipei Medical University, Taipei, Taiwan, ROC.
  • 3 Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Taipei Medical University Hospital, Taipei, Taiwan, ROC; Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan, ROC; Department of Obstetrics and Gynecology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan, ROC; Department of Obstetrics and Gynecology, School of Medicine, National Defense Medical Center, Taiwan, ROC.
  • 4 Graduate Institute of Biomedical Materials and Tissue Engineering, and International PhD Program in Biomedical Engineering, College of Biomedical Engineering, Taipei Medical University, Taipei, Taiwan, ROC; Department of Biochemistry and Molecular Cell Biology, School of Medicine, Graduate Institute of Medical Sciences, College of Medicine, Graduate Institute of Biomedical Materials and Tissue Engineering, Graduate Institute of Nanomedicine and Medical Engineering, College of Biomedical Engineering, Taipei Medical University, Taipei, Taiwan, ROC.
  • 5 Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan, ROC.
  • 6 Department of Biochemistry and Molecular Cell Biology, School of Medicine, Graduate Institute of Medical Sciences, College of Medicine, Graduate Institute of Biomedical Materials and Tissue Engineering, Graduate Institute of Nanomedicine and Medical Engineering, College of Biomedical Engineering, Taipei Medical University, Taipei, Taiwan, ROC. Electronic address: flmi530326@tmu.edu.tw.
  • 7 Graduate Institute of Biomedical Materials and Tissue Engineering, and International PhD Program in Biomedical Engineering, College of Biomedical Engineering, Taipei Medical University, Taipei, Taiwan, ROC. Electronic address: eychuang@tmu.edu.tw.
PMID: 31260820 DOI: 10.1016/j.actbio.2019.06.053
Abstract

Fibrinolytic treatments for venous or arterial thrombotic syndromes using systemic administration of thrombolytics, such as streptokinase, can induce life-threatening bleeding complications. In this study, we offer the first proof of concept for a targeted photothermal fibrin clot prevention and reduction technology using macrophages loaded with polypyrrole-polyethylenimine nanocomplexes (Ppy-PEI NCs) and subjected to near-infrared radiation (NIR). We first show that the developed Ppy-PEI NCs could be taken up by defensive macrophages in vitro through endocytosis. The Ppy-PEI NCs generated local hyperthermia upon NIR treatment, which appeared to produce Reactive Oxygen Species in Ppy-PEI NC-loaded macrophages. Preliminary evidence of efficacy as an antithrombotic tool is provided, in vitro, using fibrinogen-converted fibrin clots, and in vivo, in a rat femoral vascular thrombosis model generated by exposure to ferric chloride substance. The in vivo biocompatibility, photothermal behavior, biodistribution, and histological observation of cellular interactions with the Ppy-PEI NCs in the rat model provide rationale in support of further preclinical studies. This Ppy-PEI NC/NIR-based method, which uses a unique macrophage-guided targeting approach to prevent and lyse fibrin clots, may potentially overcome some of the disadvantages of current thrombolytic treatments. STATEMENT OF SIGNIFICANCE: Fibrinolytic treatments for venous or arterial thrombotic syndromes using systemic administration of thrombolytics, such as streptokinase, can induce life-threatening bleeding complications. In this study, we offer the first proof of concept for a targeted photothermal fibrin clot reduction technology using macrophages loaded with polypyrrole-polyethylenimine nanocomplexes (Ppy-PEI NCs) and subjected to near-infrared radiation (NIR). We first show that the developed Ppy-PEI NCs can be taken up by defensive macrophages in vitro through endocytosis. The Ppy-PEI NCs generated local hyperthermia upon NIR treatment, which appeared to produce Reactive Oxygen Species in Ppy-PEI NC-loaded macrophages. Preliminary evidence of efficacy as an antithrombotic tool is provided, in vitro, using fibrinogen-converted fibrin clots, and in vivo, in a rat femoral vascular thrombosis model generated by exposure to ferric chloride substance. The in vivo biocompatibility, photothermal behavior, biodistribution, and histological observation of cellular interactions with the Ppy-PEI NCs in the rat model provide rationale in support of further preclinical studies. This Ppy-PEI NC/NIR-based method, which uses a unique macrophage-guided targeting approach to disintegrate fibrin clots, may potentially overcome some of the disadvantages of current thrombolytic treatments.

Keywords

Macrophage; Photothermal effect; Ppy-PEI NC; ROS; Thrombolytic therapy.

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