Platelet microparticle-inspired clot-responsive nanomedicine for targeted fibrinolysis

CL Pawlowski, W Li, M Sun, K Ravichandran… - Biomaterials, 2017 - Elsevier
CL Pawlowski, W Li, M Sun, K Ravichandran, DS Hickman, C Kos, G Kaur, AS Gupta
Biomaterials, 2017Elsevier
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 …
Abstract
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-A2. 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.
Elsevier
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