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An activated-platelet-sensitive nanocarrier enables targeted delivery of tissue plasminogen activator for effective thrombolytic therapy

Huang, Y; Yu, L; Ren, J; Gu, B; Longstaff, C; Hughes, AD; Thom, SA; ... Chen, R; + view all (2019) An activated-platelet-sensitive nanocarrier enables targeted delivery of tissue plasminogen activator for effective thrombolytic therapy. Journal of Controlled Release , 300 pp. 1-12. 10.1016/j.jconrel.2019.02.033. Green open access

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Abstract

It remains a major challenge to develop a selective and effective fibrinolytic system for thrombolysis with minimal undesirable side effects. Herein, we report a multifunctional liposomal system (164.6 ± 5.3 nm in diameter) for selective thrombolysis through targeted delivery and controlled release of tissue plasminogen activator (tPA) at the thrombus site. The tPA-loaded liposomes were PEGylated to improve their stability, and surface coated with a conformationally-constrained, cyclic arginine–glycine–aspartic acid (cRGD) to enable highly selective binding to activated platelets. The in vitro drug release profiles at 37 oC showed that over 90% of tPA was released through liposomal membrane destabilization involving membrane fusion upon incubation with activated platelets within 1 h, whereas passive release of the encapsulated tPA in pH 7.4 PBS buffer was 10% after 6 h. The release of tPA could be readily manipulated by changing the concentration of activated platelets. The presence of activated platelets enabled the tPA-loaded, cRGD-coated, PEGylated liposomes to induce efficient fibrin clot lysis in a fibrin-agar plate model and the encapsulated tPA retained 97.4 ± 1.7% of fibrinolytic activity as compared with that of native tPA. Furthermore, almost complete blood clot lysis was achieved in 75 min, showing considerably higher and quicker thrombolytic activity compared to the tPA-loaded liposomes without cRGD labelling. These results suggest that the nano-sized, activated-platelet-sensitive, multifunctional liposomes could facilitate selective delivery and effective release of tPA at the site of thrombus, thus achieving efficient clot dissolution whilst minimising undesirable side effects

Type: Article
Title: An activated-platelet-sensitive nanocarrier enables targeted delivery of tissue plasminogen activator for effective thrombolytic therapy
Location: Netherlands
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.jconrel.2019.02.033
Publisher version: https://doi.org/10.1016/j.jconrel.2019.02.033
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: Activated platelet; liposome; tissue plasminogen activator; GPIIb-IIIa integrin; targeted delivery; controlled release mechanism; thrombolysis
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Cardiovascular Science
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Cardiovascular Science > Population Science and Experimental Medicine
URI: https://discovery.ucl.ac.uk/id/eprint/10070093
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