Platelet microparticle-inspired clot-responsive nanomedicine for targeted fibrinolysis.
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.
Case Western Reserve University, Department of Biomedical Engineering, Cleveland, OH 44106, USA.
Christa L
CL
Pawlowski
Cleveland Clinic Foundation, Department of Cellular and Molecular Medicine, Cleveland, OH 44195, USA.
Wei
W
Li
Case Western Reserve University, Department of Biomedical Engineering, Cleveland, OH 44106, USA.
Michael
M
Sun
Hathaway Brown School, Shaker Heights, OH 44122, USA.
Kavya
K
Ravichandran
Case Western Reserve University, Department of Biomedical Engineering, Cleveland, OH 44106, USA.
DaShawn
D
Hickman
Case Western Reserve University, Department of Biomedical Engineering, Cleveland, OH 44106, USA.
Clarissa
C
Kos
Hathaway Brown School, Shaker Heights, OH 44122, USA.
Gurbani
G
Kaur
Case Western Reserve University, Department of Biomedical Engineering, Cleveland, OH 44106, USA. Electronic address: axs262@case.edu.
Anirban
A
Sen Gupta
D000818:Animals; D001792:Blood Platelets / Q000166:cytology*; D055252:Cell-Derived Microparticles / Q000378:metabolism*; D005342:Fibrinolysis / Q000187:drug effects; D005343:Fibrinolytic Agents / Q000494:pharmacology / Q000627:therapeutic use; D000069416:Intravital Microscopy; D008049:Lipase / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D050997:Nanomedicine / Q000379:methods*; D010455:Peptides / Q000378:metabolism; D054467:Phospholipases A2 / Q000378:metabolism; D012995:Solubility; D013927:Thrombosis / Q000188:drug therapy / Q000473:pathology / Q000628:therapy*
D005343:Fibrinolytic Agents; D010455:Peptides; D008049:Lipase; D054467:Phospholipases A2
Drug delivery; Enzyme-triggered release; Lipid vesicle; Nanomedicine; Platelet-derived microparticle; Targeted thrombolysis