International Journal of Nanomedicine (Nov 2022)

A Synergistic and Efficient Thrombolytic Nanoplatform: A Mechanical Method of Blasting Combined with Thrombolytic Drugs

  • Hu L,
  • Xu J,
  • Zhang W,
  • Wang J,
  • Fang N,
  • Luo Y,
  • Xu L,
  • Liu J,
  • Zhang Y,
  • Ran H,
  • Guo D,
  • Zhou J

Journal volume & issue
Vol. Volume 17
pp. 5229 – 5246

Abstract

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Liu Hu1,2 *, Jie Xu1 *, Wenli Zhang,1,2 Junrui Wang,1,2 Ni Fang,1,2 Ying Luo,1,2 Lian Xu,1,2 Jia Liu,1 Yu Zhang,1 Haitao Ran,3 Dajing Guo,1 Jun Zhou1 1Department of Radiology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of China; 2Chongqing Key Laboratory of Ultrasound Molecular Imaging & Department of Ultrasound, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of China; 3Department of Ultrasound, Institute of Ultrasound Imaging, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jun Zhou, Tel +86 23 6288 7295, Email [email protected] and Objective: Thrombosis is a common disease that poses a great threat to life and health. Most thrombolytic effects of traditional treatments or nanomedicine are not efficient or safe enough. Therefore, we designed a nanoparticle (NP) with a combination of a phase transition material and thrombolytic drugs for efficient and safe thrombolysis.Methods: A thrombus fibrin-targeted and phase transition NP was designed and contained perfluorohexane (PFH) and the thrombolytic drug rtPA core, with CREKA polypeptides attached to the shell of the PLGA NPs. Characterization of the phase transition and ultrasound imaging of the NPs was carried out under low-intensity focused ultrasound (LIFU). LIFU-responsive drug release in vitro was also explored. Under the synergistic effect of PFH and rtPA, the efficient thrombolysis ability of the NPs was studied in vitro and in vivo. In vivo monitoring of thrombosis and biosafety were also verified.Results: The PPrC NPs had good ultrasound imaging ability under LIFU irradiation and were related to the phase transition characteristics of the NPs. CREKA polypeptides can effectively increase the aggregation of the NPs on thrombi. Under static and dynamic conditions in vitro, the “liquid to gas” transformation effect of PFH can perform the destruction function of the excavator at the thrombus site and promote the specific release of rtPA, and the subsequent rtPA drug thrombolysis can further fully dissolve the thrombus. In vivo experiments showed that the NPs can monitor the formation of thrombi and have good thrombolytic effects, with significantly reduced bleeding side effects. The biochemical indexes of the rats were within normal limits after treatment.Conclusion: PPrC NPs loaded with PFH and rtPA combining a mechanical way of blasting with thrombolytic drugs may be a promising new and reliable approach for thrombus monitoring and treatment.Keywords: low-intensity focused ultrasound, thrombolysis, PFH, rtPA, phase transition

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