A chimeric platelet-targeted urokinase prodrug selectively blocks new thrombus formation

Fuentes, Rudy; Зайцев, С. В.; Ahn, Hyun Sook; Hayes, Vincent; Kowalska, M. Anna; Lambert, Michele P.; Wang, Yuhuan; Siegel, Donald L.; Bougie, Daniel W.; Aster, Richard H.; Myers, Daniel D.; Stepanova, Victoria; Cines, Douglas B.; Muzykantov, Vladimir R.; Poncz, Mortimer

doi:10.1172/jci81470

Cited by 28 publications

(24 citation statements)

References 34 publications

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“…[48][49][50][51][52] Our priority was to establish a comparatively straightforward model, suitable for testing and comparing targeted scFv/TM with other antithrombotic drugs. 18,[53][54][55] Although the model lacks subendothelial components of a true vessel, including epithelial tissues, it allows for control over endothelial and leukocyte activation, manipulation and treatment of human WB, and quantification of therapeutic effects with high spatial and temporal resolution. While the present focus was on abrogation of fibrin deposition, additional readouts of inflammatory biology such as leukocyte adhesion and generation of neutrophil extracellular traps were also shown to be possible using this model system.…”

Section: Discussionmentioning

confidence: 99%

ICAM-1–targeted thrombomodulin mitigates tissue factor–driven inflammatory thrombosis in a human endothelialized microfluidic model

Greineder¹,

Johnston

Villa

et al. 2017

Blood Advances

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Section: Discussionmentioning

confidence: 99%

ICAM-1–targeted thrombomodulin mitigates tissue factor–driven inflammatory thrombosis in a human endothelialized microfluidic model

Greineder¹,

Johnston

Villa

et al. 2017

Blood Advances

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“…platelet-specific or fibrin-specific) antibodies and ligands [30–35]. While encapsulation of thrombolytic agents within micro and nanoparticles may increase their circulatory safety and residence time, that may not ensure their preferential delivery and release at the clot site.…”

Section: Discussionmentioning

confidence: 99%

Platelet microparticle-inspired clot-responsive nanomedicine for targeted fibrinolysis

et al. 2017

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Intravascular administration of plasminogen activators is a clinically important thrombolytic strategy to treat occlusive vascular conditions. A major issue with this strategy is the systemic off-target drug action, which affects hemostatic capabilities and causes substantial hemorrhagic risks. This issue can be potentially resolved by designing technologies that allow thrombus-targeted delivery and site-specific action of thrombolytic drugs. To this end, leveraging a liposomal platform, we have developed platelet microparticle (PMP)-inspired nanovesicles (PMINs), that can protect encapsulated thrombolytic drugs in circulation to prevent off-target uptake and action, anchor actively onto thrombus via PMP-relevant molecular mechanisms and allow drug release via thrombus-relevant enzymatic trigger. Specifically, the PMINs can anchor onto thrombus via heteromultivalent ligand-mediated binding to active platelet integrin GPIIb-IIIa and P-selectin, and release the thrombolytic payload due to vesicle destabilization triggered by clot-relevant enzyme phospholipase-A. Here we report on the evaluation of clot-targeting efficacy, lipase-triggered drug release and resultant thrombolytic capability of the PMINs in vitro, and subsequently demonstrate that intravenous delivery of thrombolytic-loaded PMINs can render targeted fibrinolysis without affecting systemic hemostasis, in vivo, in a carotid artery thrombosis model in mice. Our studies establish significant promise of the PMIN technology for safe and site-targeted nanomedicine therapies in the vascular compartment.

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“…The cremaster muscle was surgically exteriorized and continuously superfused with a physiological buffer (PBS containing 0.9 mM CaCl 2 and 0.49 mM MgCl 2 ) maintained at 37°C throughout the entire experiment and equilibrated with a mixture of 95% N2 and 5% CO2. Human platelets, 400 million per mouse, were labeled with mouse anti-human CD41 F(ab′)2 (BD Biosciences) conjugated to Alexa Fluor-488 and infused into the jugular vein, followed by Alexa Fluor-647 rat anti-mouse CD41 F(ab′)2 (Thermo Fisher) to detect endogenous mouse platelets 65 . Vascular injury was induced with an SRS NL100 pulsed nitrogen dye laser (440 nm) focused on the vessel wall through the microscope objective.…”

Section: Plasmids Mutagenesis Protein Expression Purification and mentioning

confidence: 99%

Structure-guided design of a pure orthosteric antagonist of integrin αlIbβ3 that inhibits thrombosis but not clot retraction

Adair

Alonso

Agthoven

et al. 2018

Preprint

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Platelet integrin αlIbβ3 plays a critical role in both hemostasis and thrombosis. Current αIIbβ3 antagonists are potent anti-thrombotic drugs, but also cause adverse outcomes, which limited their clinical use. Drug-induced serious bleeding, thrombocytopenia and paradoxical thrombosis have been linked to impaired clot retraction and to conformational changes in αIIbβ3 that promote binding of preformed antibodies, natural ligands or both to αIIbβ3. We have used structure-guided design to generate the orthosteric inhibitor Hr10 that acts as a pure αIIbβ3 antagonist, i.e. it does not induce the conformational changes in αIIbβ3. Hr10 is as effective as the partial agonist drug eptifibatide in blocking platelet aggregation and arteriolar thrombosis in mice. In contrast to eptifibatide, however, Hr10 preserved thrombin-induced clot retraction, suggesting that it may not perturb hemostasis. Our structure-based approach can find general utility in designing pure orthosteric inhibitors for other integrins, in providing vital tools for dissecting structure-activity relationships in αIIbβ3, and potentially in offering safer alternatives for human therapy.

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A chimeric platelet-targeted urokinase prodrug selectively blocks new thrombus formation

Cited by 28 publications

References 34 publications

ICAM-1–targeted thrombomodulin mitigates tissue factor–driven inflammatory thrombosis in a human endothelialized microfluidic model

ICAM-1–targeted thrombomodulin mitigates tissue factor–driven inflammatory thrombosis in a human endothelialized microfluidic model

Platelet microparticle-inspired clot-responsive nanomedicine for targeted fibrinolysis

Structure-guided design of a pure orthosteric antagonist of integrin αlIbβ3 that inhibits thrombosis but not clot retraction

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