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

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Huang et al. Journal of Controlled Release 2019_Accepted Manuscript.pdfFile embargoed until 23 February 20207.41 MBAdobe PDF    Request a copy
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Title: An activated-platelet-sensitive nanocarrier enables targeted delivery of tissue plasminogen activator for effective thrombolytic therapy
Authors: Huang, Y
Yu, L
Ren, J
Gu, B
Longstaff, C
Hughes, AD
Thom, SA
Xu, XY
Chen, R
Item Type: Journal Article
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) which can address this challenge 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 °C 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.
Issue Date: 28-Apr-2019
Date of Acceptance: 21-Feb-2019
ISSN: 0168-3659
Publisher: Elsevier
Start Page: 1
End Page: 12
Journal / Book Title: Journal of Controlled Release
Volume: 300
Copyright Statement: © 2019 Elsevier Ltd. All rights reserved. This manuscript is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International Licence
Sponsor/Funder: Imperial College Healthcare NHS Trust- BRC Funding
Funder's Grant Number: RDB02
Keywords: Activated platelet
Controlled release mechanism
GPIIb-IIIa integrin
Targeted delivery
Tissue plasminogen activator
0903 Biomedical Engineering
1115 Pharmacology And Pharmaceutical Sciences
Pharmacology & Pharmacy
Publication Status: Published
Conference Place: Netherlands
Embargo Date: 2020-02-23
Online Publication Date: 2019-02-23
Appears in Collections:Faculty of Engineering
National Heart and Lung Institute
Chemical Engineering
Faculty of Medicine

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