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 under development.
“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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- 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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