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 ... More
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.
