Temperature-sensitive liposome-mediated delivery of thrombolytic agents.

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  • Author(s): Saxena V;Saxena V; Gacchina Johnson C; Negussie AH; Sharma KV; Dreher MR; Wood BJ
  • Source:
    International journal of hyperthermia : the official journal of European Society for Hyperthermic Oncology, North American Hyperthermia Group [Int J Hyperthermia] 2015 Feb; Vol. 31 (1), pp. 67-73. Date of Electronic Publication: 2015 Mar 13.
  • Publication Type:
    Journal Article; Research Support, N.I.H., Extramural; Research Support, N.I.H., Intramural; Research Support, Non-U.S. Gov't
  • Language:
    English
  • Additional Information
    • Source:
      Publisher: Informa Healthcare Country of Publication: England NLM ID: 8508395 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1464-5157 (Electronic) Linking ISSN: 02656736 NLM ISO Abbreviation: Int J Hyperthermia Subsets: MEDLINE
    • Publication Information:
      Publication: London : Informa Healthcare
      Original Publication: London ; Philadelphia : Taylor & Francis, c1985-
    • Subject Terms:
      Blood Coagulation/*drug effects ; Fibrinolytic Agents/*administration & dosage ; Metalloendopeptidases/*administration & dosage ; Tissue Plasminogen Activator/*administration & dosage ; Urokinase-Type Plasminogen Activator/*administration & dosage; Humans ; Hyperthermia, Induced ; Lipids/chemistry ; Liposomes ; Male ; Metalloendopeptidases/chemistry ; Polyethylene Glycols/chemistry ; Temperature ; Tissue Plasminogen Activator/chemistry ; Urokinase-Type Plasminogen Activator/chemistry
    • Abstract:
      Background: Clinical efficacy of thrombolytic drugs is limited by lack of specific delivery and requires large therapeutic doses which increase toxicity. Encapsulating these drugs in temperature-sensitive liposomes and applying hyperthermia to deliver thrombolytic agents locally to thrombus might theoretically favourably alter the therapeutic window. The objectives of this study were to formulate liposomes encapsulating thrombolytics and assess thrombolytic activity following hyperthermia.
      Methods: Three liposome formulations were investigated: temperature-sensitive liposome (TSL, DPPC:DSPE-PEG2000 (mol% 95:5)), low temperature-sensitive liposome (LTSL, DPPC:MSPC:DSPE-PEG2000 (mol% 85.3:9.7:5)), and traditional temperature-sensitive liposome (TTSL, DPPC:HSPC:Chol:DSPE-PEG2000 (mol% 55:25:15:5)). To characterise temperature-dependent release of high molecular weight cargo from each formulation, fluorescein-conjugated dextrans (70 kDa) were loaded and release was quantified via spectrophotometry. Staphylokinase (SAK), urokinase, and tissue-type plasminogen activator were also loaded individually into each liposome formulation. Leakage at 37 °C and release at 38-44 °C were quantified via chromogenic enzymatic activity assay. Clot lysis was evaluated by measuring mass of blood clots before and after thrombolytic liposome treatment.
      Results: The LTSL formulation had optimal release characteristics with maximum release at 41.3 °C. Release of dextrans from LTSLs was observed to be 11.5 ± 1.5%, 79.7 ± 1.6%, and 93.6 ± 3.7% after 15 min in plasma at 37°, 39°, and 41.3 °C, respectively. The SAK LTSL had the highest release/leakage ratio and demonstrated greater clot lysis.
      Conclusions: The SAK LTSL achieves significant clot lysis in vitro. When combined with local hyperthermia, the SAK LTSL potentially produces sufficient thrombolysis while minimising systemic side effects.
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    • Grant Information:
      Z99 CL999999 United States Intramural NIH HHS; United States Howard Hughes Medical Institute
    • Contributed Indexing:
      Keywords: Staphylokinase; temperature sensitive liposomes; thrombolysis; tissue plasminogen activator
    • Accession Number:
      0 (Fibrinolytic Agents)
      0 (Lipids)
      0 (Liposomes)
      3WJQ0SDW1A (Polyethylene Glycols)
      EC 3.4.21.68 (Tissue Plasminogen Activator)
      EC 3.4.21.73 (Urokinase-Type Plasminogen Activator)
      EC 3.4.24.- (Metalloendopeptidases)
      EC 3.4.24.29 (auR protein, Staphylococcus aureus)
    • Publication Date:
      Date Created: 20150314 Date Completed: 20151223 Latest Revision: 20191008
    • Publication Date:
      20221213
    • Accession Number:
      PMC5528861
    • Accession Number:
      10.3109/02656736.2014.991428
    • Accession Number:
      25766387