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Nanomedicine. 2018 Apr;14(3):633-642. doi: 10.1016/j.nano.2017.12.022. Epub 2018 Jan 6.

A targeted ferritin-microplasmin based thrombolytic nanocage selectively dissolves blood clots.

Author information

1
Department of Biochemistry and Cell Biology, Cell and Matrix Research Institute, School of Medicine, Kyungpook National University, Daegu, Republic of Korea.
2
Biomedical Research Institute, Korea Institute of Science and Technology, Seoul, Republic of Korea; Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, Texas, USA.
3
College of Pharmacy, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu, Republic of Korea.
4
Department of Internal Medicine, Kyungpook National University School of Medicine, Daegu, Republic of Korea.
5
Department of Physiology, School of Medicine, Kyungpook National University, Daegu, Republic of Korea.
6
Department of Biochemistry and Cell Biology, Cell and Matrix Research Institute, School of Medicine, Kyungpook National University, Daegu, Republic of Korea. Electronic address: soyounki@knu.ac.kr.
7
Biomedical Research Institute, Korea Institute of Science and Technology, Seoul, Republic of Korea; KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul, Republic of Korea. Electronic address: iskim14@kist.re.kr.

Abstract

The use of thrombolytic therapies is limited by an increased risk of systemic hemorrhage due to lysis of hemostatic clots. We sought to develop a plasmin-based thrombolytic nanocage that efficiently dissolves the clot without causing systemic fibrinolysis or disrupting hemostatic clots. Here, we generated a double chambered short-length ferritin (sFt) construct that has an N-terminal region fused to multivalent clot targeting peptides (CLT: CNAGESSKNC) and a C-terminal end fused to a microplasmin (μPn); CLT recognizes fibrin-fibronectin complexes in clots, μPn efficiently dissolves clots, and the assembly of double chambered sFt (CLT-sFt-μPn) into nanocage structure protects the activated-μPn from its circulating inhibitors. Importantly, activated CLT-sFt-μPn thrombolytic nanocage showed a prolonged circulatory life over activated-μPn and efficiently lysed the preexisting clots in both arterial and venous thromboses models. Thus, CLT-sFt-μPn thrombolytic nanocage platform represents the prototype of a targeted clot-busting agent with high efficacy and safety over existing thrombolytic therapies.

KEYWORDS:

Clot targeting peptide; Ferritin; Microplasmin; Nanoparticle; Thrombolysis

PMID:
29309907
DOI:
10.1016/j.nano.2017.12.022
[Indexed for MEDLINE]

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