title: Ultrasound-responsive thrombus treatment with zinc-stabilized gelatin nano-complexes of tissue-type plasminogen activator.
abstract: 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.
authors.affiliation: Department of Biomaterials, Field of Tissue Engineering, Institute for Frontier Medical Sciences, Kyoto University, Kawara-cho Shogoin, Sakyo-ku, Kyoto, Japan.
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Uesugi
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kawata
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Saito
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Tabata
mesh_terms: D000818:Animals; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004337:Drug Carriers / Q000008:administration & dosage* / Q000009:adverse effects / Q000378:metabolism / Q000493:pharmacokinetics; D004339:Drug Compounding; D004789:Enzyme Activation; D005260:Female; D005343:Fibrinolytic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000378:metabolism / Q000493:pharmacokinetics; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D005780:Gelatin / Q000009:adverse effects / Q000737:chemistry; D006207:Half-Life; D051379:Mice; D008815:Mice, Inbred Strains; D053758:Nanoparticles / Q000009:adverse effects / Q000737:chemistry*; D011310:Preservatives, Pharmaceutical / Q000009:adverse effects / Q000737:chemistry; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000009:adverse effects / Q000378:metabolism / Q000493:pharmacokinetics; D013016:Sound; D015912:Thrombolytic Therapy / Q000009:adverse effects / Q000379:methods*; D010959:Tissue Plasminogen Activator / Q000008:administration & dosage* / Q000009:adverse effects / Q000378:metabolism / Q000493:pharmacokinetics; D019345:Zinc Acetate / Q000009:adverse effects / Q000737:chemistry*
chemical_list: D004337:Drug Carriers; D005343:Fibrinolytic Agents; D011310:Preservatives, Pharmaceutical; D011994:Recombinant Proteins; D005780:Gelatin; D010959:Tissue Plasminogen Activator; D019345:Zinc Acetate