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Urokinase-coated chitosan nanoparticles for thrombolytic therapy: preparation and pharmacodynamics in vivo

Abstract

Blood reperfusion of affected limbs is the most effective therapy for peripheral vascular thrombotic disease, restoring nutrition and blood flow to threatened tissues. Because it is more cost-effective than other thrombolytics, urokinase (UK) is widely used to treat venous thrombosis in China. However, its use is limited because of the risk of UK-related hemorrhagic complications. UK-coated nanoparticles (NPs) may decrease adverse effects while simultaneously increasing thrombolytic benefits. The aim of this study was to combine the sustained-release properties of NPs with the clinical benefits of catheter-directed thrombolysis (CDT) to create a promising new therapy. NPs were prepared via self-assembled chitosan and tripolyphosphate, introduced into a thrombosis model in New Zealand white rabbits, and the ratio of the residual thrombus cross-sectional area to the vascular cross-sectional area was calculated. The NPs had a drug-bearing efficiency of 14.5 ± 1.3 %, an encapsulation efficiency of 94.8 ± 2.1 % while the particle size of UK-coated NPs was 236 nm. Transmission electron microscopy results showed that the shape of the NPs were spherical and regular. Whether delivered by intravenation or catheter, UK-coated NPs produced a significant increase in the thrombolytic effect compared with free UK and confirmed the superiority of CDT for improving clot lysis over drug-induced systemic thrombolysis. The intravenous NPs caused an abnormal increase in fibrinogen. In conclusion, a water-soluble UK-WCS-NP suspension with good encapsulation efficiency was easily prepared UK-WCS-NPs were capable of maintaining UK activity, provided sustained-release of UK and exhibited better thrombolytic function than free UK.

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Abbreviations

CDT:

Catheter-directed thrombolysis

CS:

Chitosan

ELISA:

Enzyme linked immunosorbent assay

IV:

Intravenation

MW:

Molecular weight

NP:

Nanoparticle

PBS:

Phosphate-buffered saline

SEM:

Standard error of mean

SPSS:

Statistical Product and Service Solutions

TEM:

Transmission electron microscope

TPP:

Tripolyphosphate

UK:

Urokinase

UK-WCS-NP:

Water-soluble urokinase-loaded chitosan nanoparticle

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Acknowledgments

This work was supported by the Science and Technology Commission of Shanghai Municipality, China (0852nm05100). The authors wish to thank Medjaden Bioscience Limited and Professor Shun-xing Zhang for critical review of the manuscript. We also thank the Clinical Laboratory of RENJI Hospital attached to Shanghai Jiaotong University School of Medicine.

Conflict of interest

No conflicts.

Author information

Correspondence to Hao Zhang.

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Jin, H., Zhang, H., Sun, M. et al. Urokinase-coated chitosan nanoparticles for thrombolytic therapy: preparation and pharmacodynamics in vivo. J Thromb Thrombolysis 36, 458–468 (2013). https://doi.org/10.1007/s11239-013-0951-7

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Keywords

  • Urokinase
  • Nanoparticles
  • Thrombolytic
  • Sustained-release
  • Water-soluble chitosan