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An ultrasound-responsive nano delivery system of tissue-type plasminogen activator for thrombolytic therapy
Abstract
This study is undertaken to design a novel nano-sized delivery system of tissue-type plasminogen activator (t-PA) which has a suppressed thrombolytic activity of t-PA, but recovered the activity only when exposed to ultrasound. Various amounts of ethylenediamine were chemically introduced into gelatin (cationized gelatins) to complex with t-PA. To modify the surface of complexes with polyethylene glycol (PEG), PEG was chemically grafted to the anionic gelatin (PEG-gelatin). The simple mixing with the PEG-gelatin enabled the t-PA-cationized gelatin complex to form a nano-sized delivery complex with PEG chains on the surface. The t-PA activity of PEG-modified complexes was significantly suppressed to be 45% of original t-PA. However, when exposed to ultrasound in vitro, the t-PA activity was fully recovered. A cell culture experiment demonstrated no cytotoxicity of PEG-modified complexes. The body distribution study indicated that the half-life of t-PA in the blood circulation was prolonged about 3 times. In a rabbit thrombosis model, the intravenous administration of PEG-modified complexes followed by ultrasound irradiation resulted in complete recanalization, in remarked contrast to the complex administration alone. It is concluded that the PEG-modified complex is a promising t-PA delivery system to enhance the biological activity at the site necessary only by a local ultrasound irradiation.
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“Nanoparticles designed to induce acute thrombolysis of thrombotic occlusions caused by ruptured plaques are also under development114,115.”
From Perspectives and opportunities for nanomedicine in the management of atherosclerosis (2011) · cites this paper as [115]
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Metadata
- Authors
- Uesugi, Y., Kawata, H., Jo, J.-I., Saito, Y., & Tabata, Y.
- Affiliations
- Kyoto University (JP)
- Nara Medical University (JP)
- Corresponding author
- Tabata, Yasuhiko
- Venue
- Journal of Controlled Release
- Publisher
- Elsevier BV
- Published
- 2010-10
- Volume
- 147
- Issue
- 2
- Pages
- 269-277
- ISSN
- 0168-3659 (ISSN-L)
- OpenAlex
- W1966250539
- Cited by
- 103
- References
- 81
- Citations by year
- 2026: 3 · 2025: 4 · 2024: 6 · 2023: 4 · 2022: 6 · 2021: 9 · 2020: 8 · 2019: 12 · 2018: 2 · 2017: 8 · 2016: 6 · 2015: 7 · 2014: 9 · 2013: 8 · 2012: 6
- FWCI
- 3.59
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- Journal of Controlled Release (publishedVersion)
- PubMed (publishedVersion)
- Institutional Repositories DataBase (IRDB) (submittedVersion)
- Kyoto University Research Information Repository (Kyoto University) (submittedVersion)
- Funders
- National Institute of Biomedical Innovation
- Topics
- Physical Sciences › Engineering › Biomedical Engineering › Ultrasound and Hyperthermia Applications
- Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmaceutical Science › Advanced Drug Delivery Systems
- Keywords
- tissue plasminogen activator, thrombolysis, ultrasound-responsive drug delivery, ethylenediamine, polyethylene glycol, PEGylation, thrombosis recanalization, blood circulation half-life, cytotoxicity
- MeSH terms
- Animals, Cell Line, Cell Survival, Disease Models, Animal, Drug Carriers, Ethylenediamines, Fibrinolytic Agents, Fibroblasts, Gelatin, Tissue Plasminogen Activator, Polyethylene Glycols, Rabbits, Surface Properties, Thrombosis, Tissue Distribution, Ultrasonic Therapy, Mice, Nanoparticles
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