Platelet microparticle-inspired clot-responsive nanomedicine for targeted fibrinolysis

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-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.

Trauma‐targeted delivery of tranexamic acid improves hemostasis and survival in rat liver hemorrhage model

“…We used unilamellar liposomal vesicles as a model delivery system 61,62 and decorated its surface ). [63][64][65] The 100% survival of T-tNV-treated rats within the first hour (and continued improved survival over 72 hours) is very promising, considering that most preventable mortalities from traumatic hemorrhage occur within few hours of injury. 4,6 Interestingly, free TXA-treated rats did not perform as well as T-tNV-treated rats, suggesting possible off-target effects or reduced bioavailability at the hemorrhaging injury site.…”

Engineered microparticles and nanoparticles for fibrinolysis

“…In the ferric chloride thrombosis model in the murine carotid artery the SK‐PMIN had antithrombotic properties indistinguishable from an equal dose of free SK. In a murine tail bleeding model, the bleeding times for mice treated with SK‐PMIN are equivalent to those for untreated controls, while bleeding times for mice receiving free SK were threefold higher . Unlike free SK, these SK‐PMIN do not initiate systemic fibrinogenolysis.…”

“…In a murine tail bleeding model, the bleeding times for mice treated with SK-PMIN are equivalent to those for untreated controls, while bleeding times for mice receiving free SK were threefold higher. 52 Unlike free SK, these SK-PMIN do not initiate systemic fibrinogenolysis.…”

“…Pawlowski et al. designed platelet microparticle‐inspired nanovesicles (PMIN) carrying SK that interact with platelets via ligands for α IIb β 3 and P‐selectin . Once the PMIN interacts with platelets, phospholipase A 2 , an enzyme that is upregulated in sclerotic arteries, destabilizes the PMIN and triggers release of SK.…”

“…Another targeting and triggered-release strategy relies on imitating or hijacking platelets or red blood cells (RBC) ( Figure 1 carrying SK that interact with platelets via ligands for α IIb β 3 and P-selectin. 52 Once the PMIN interacts with platelets, phospholipase A 2 , an enzyme that is upregulated in sclerotic arteries, 53 destabilizes the PMIN and triggers release of SK. In the ferric chloride thrombosis model in the murine carotid artery the SK-PMIN had antithrombotic properties indistinguishable from an equal dose of free SK.…”