Thrombus-specific theranostic nanocomposite for codelivery of thrombolytic drug, algae-derived anticoagulant and NIR fluorescent contrast agent

Thrombolysis is a standard treatment for rapidly restoring blood flow. However, the application of urokinase-type plasminogen activator (Uk) in clinical therapy is limited due to its nonspecific distribu-tion and inadequate therapeutic accumulation. Precise thrombus imaging and site-specific drug deliv-ery can enhance the diagnostic and therapeutic efficacy for thrombosis. Accordingly, we developed a P-selectin-specific, photothermal theranostic nanocomposite for thrombus-targeted codelivery of Uk and indocyanine green (ICG, a contrast agent for near-infrared (NIR) fluorescence imaging). We evaluated its capabilities for thrombus imaging and enzyme/hyperthermia combined thrombolytic therapy. Meso-porous silica-coated gold nanorods (Si-AuNRs) were functionalized with an arginine-rich peptide to cre-ate an organic template for the adsorption of ICG and fucoidan (Fu), an algae-derived anticoagulant. Uk was loaded into the SiO2 pores of the Si-AuNRs through the formation of a Fu-Uk-ICG complex on the peptide-functionalized template. The Fu-Uk/ICG@SiAu NRs nanocomposite increased the photostability of ICG and improved its targeting/accumulation at blood clot sites with a strong NIR fluorescence inten-sity for precise thrombus imaging. Furthermore, ICG incorporated into the nanocomposite enhanced the photothermal effect of Si-AuNRs. Fu, as a P-selectin-targeting ligand, enabled the nanocomposite to tar -get a thrombus site where platelets were activated. The nanocomposite enabled a faster release of Uk for rapid clearing of blood clots and a slower release of Fu for longer lasting prevention of thrombo-sis regeneration. The nanocomposite with multiple functions, including thrombus-targeting drug delivery, photothermal thrombolysis, and NIR fluorescence imaging, is thus an advanced theranostic platform for thrombolytic therapy with reduced hemorrhaging risk and enhanced imaging/thrombolysis efficiency. Statement of significance Herein, for the first time, a P-selectin specific, photothermal theranostic nanocomposite for thrombus-targeted co-delivery of urokinase and NIR fluorescence contrast agent indocyanine green (ICG) was de-veloped. We evaluated the potential of this theranostic nanocomposite for thrombus imaging and en-zyme/hyperthermia combined thrombolytic therapy. The nanocomposite showed multiple functions in- cluding thrombus targeting and imaging, and photothermal thrombolysis. Besides, it allowed faster re- lease of the thrombolytic urokinase for rapidly clearing blood clots and slower release of a brown algae- derived anticoagulant fucoidan (also acting as a P-selectin ligand) for prevention of thrombosis regen- eration. The nanocomposite is thus a new and advanced theranostic platform for targeted thrombolytic therapy. (c) 2021 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Automated summary

A novel photothermal theranostic nanocomposite for thrombus-targeted delivery of urokinase and near-infrared fluorescence contrast agent indocyanine green (ICG) was developed, showing potential for precise thrombus imaging and enzyme/hyperthermia combined thrombolytic therapy. The nanocomposite has multiple functions including thrombus targeting, imaging, and photothermal thrombolysis, making it an advanced platform for targeted thrombolytic therapy.