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Fibrinogen-mimicking, multi-arm nanovesicles for human thrombus-specific delivery of tissue plasminogen activator and targeted thrombolytic therapy

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Title: Fibrinogen-mimicking, multi-arm nanovesicles for human thrombus-specific delivery of tissue plasminogen activator and targeted thrombolytic therapy
Authors: Huang, Y
Gu, B
Salles, II
Taylor, KA
Yu, L
Ren, J
Liu, X
Emerson, M
Longstaff, C
Hughes, AD
Thom, SA
Xu, XY
Chen, R
Item Type: Journal Article
Abstract: Clinical use of tissue plasminogen activator (tPA) in thrombolytic therapy is limited by its short circulation time and hemorrhagic side effects. Inspired by fibrinogen binding to activated platelets, we report a fibrinogen-mimicking, multi-arm nanovesicle for thrombus-specific tPA delivery and targeted thrombolysis. This novel system is based on the lipid nanovesicle coated with polyethylene glycol (PEG) terminally conjugated with a cyclic RGD (cRGD) peptide. Our experiments with human blood demonstrated its highly selective binding to activated platelets and efficient tPA release at a thrombus site under both static and physiological flow conditions. Its clot dissolution time in a microfluidic system was comparable to that of free tPA. Furthermore, we report a purpose-built computational model capable of simulating targeted thrombolysis of the tPA-loaded nanovesicle and with potential in predicting the dynamics of thrombolysis in physiologically realistic scenarios. This combined experimental and computational work presents a promising platform for development of thrombolytic nanomedicines.
Issue Date: 2-Jun-2021
Date of Acceptance: 14-Apr-2021
URI: http://hdl.handle.net/10044/1/89297
DOI: 10.1126/sciadv.abf9033
ISSN: 2375-2548
Publisher: American Association for the Advancement of Science
Journal / Book Title: Science Advances
Volume: 7
Issue: 23
Copyright Statement: © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY). https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Sponsor/Funder: Imperial College Healthcare NHS Trust- BRC Funding
Engineering & Physical Science Research Council (EPSRC)
Funder's Grant Number: RDB02
EP/R013764/1
Publication Status: Published
Article Number: ARTN eabf9033
Appears in Collections:Department of Immunology and Inflammation
National Heart and Lung Institute
Chemical Engineering
Faculty of Medicine
Faculty of Engineering



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