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Ultrasound-responsive thrombus treatment with zinc-stabilized gelatin nano-complexes of tissue-type plasminogen activator

This study is undertaken to design zinc-stabilized gelatin nano-complexes of tissue-type plasminogen activator (t-PA) for thrombolytic therapy where the t-PA activity can be recovered in the blood circulation upon ultrasound irradiation. Various molecular weights of gelatin were complexed with t-PA by their simply mixing in aqueous solution. Then, zinc acetate, calcium acetate or magnesium acetate was added to form nano-sized gelatin−t-PA complexes. The complexes had the apparent molecular size of about 100 nm. When zinc ions were added to the gelatin−t-PA complexes, the t-PA activity was suppressed most strongly to 57% of the original, free t-PA activity. Upon ultrasound exposure in vitro, the t-PA activity was fully recovered. A cell culture experiment with L929 fibroblasts demonstrated no cytotoxicity of complexes at the concentration used for the in vivo experiment. The half-life of t-PA in the blood circulation prolonged by the complexation with gelatin and zinc ions. The zinc-stabilized t-PA−gelatin complex is a promising t-PA delivery system which can manipulate the thrombolytic activity by the local ultrasound irradiation.