| Engineering devices to measure and/or enhance fibrinolysis Dante Disharoon. |
Abstract
Bioinspired Nanotherapeutics for Targeted and Enhanced Thrombolysis
Dante Disharoon1, Shruti Raghunathan1, Keren Hu1, Selvin Hernandez1, Wei Li2, Prithu Sundd3, Jordan Shavit4, Anirban Sen Gupta1
1Case Western Reserve University, Cleveland, OH
2Marshall University, Huntington, WV
3Versiti Blood Research Institute, Milwaukee, WI
4University of Michigan, Ann Arbor, MI
Thrombosis, the pathological formation of blood clots, is the underlying process behind leading causes of death and morbidity including stroke, myocardial infarction, deep vein thrombosis, pulmonary embolism, and limb ischemia. Thrombolysis, the biochemical remediation of thrombi, relies on plasminogen activators (PAs), clot busting drugs characterized by short circulation time, a poor safety profile, and poor efficacy. To overcome these limitations, we have engineered liposomal nanoparticles (LNP) that can protect PA from clearance and achieve targeted delivery of high concentrations of PA locally to the site of a blood clot. Our LNP incorporate lipid-peptide conjugates which target LNP to components of thrombi such as activated platelets, fibrin, or neutrophil extracellular traps (NETs). Heteromultivalent LNP, LNP capable of binding to multiple different ligands within a clot, exhibit greater binding avidity and extended retention time compared to LNP with a single target. Moreover, LNP are susceptible to cleavage by enzymes upregulated at the site of a thrombus, enabling site-specific triggered payload release. In several animal models, LNP exhibit thrombolytic potency while mitigating off-target bleeding compared to systemically administered PA. An additional advantage of LNP is that they can be administered in a modular fashion; in vitro, LNP delivering PA and deoxyribonuclease in parallel enhanced lysis of NET-rich clots recalcitrant to PA therapy. LNP may offer a safe and efficacious alternative for PA delivery, broadening the indications for biochemical thrombolysis.
No part of this publication may be reproduced, distributed, or transmitted in any form or by any means, including photocopying, recording, or other electronic or mechanical methods, without the prior written permission of the author.