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Optimizing antithrombotic therapy
Antiplatelet drugs are used for preventing and treating thrombotic diseases. However, they have serious adverse effects, including risk of excessive bleeding. A synthetic peptide (mP6) targeting the integrin signaling has been shown to inhibit thrombosis without affecting bleeding. Its application was hindered by inefficient and impractical intracellular delivery. Now, Pang et al. developed lipid-stabilized, high-loading peptide nanoparticles (HLPNs) for efficient in vivo delivery of the antithrombotic peptide. Injection of HLPNs loaded with engineered mP6 prevented thrombosis without affecting bleeding in mice and had therapeutic effects in a model of ischemia-reperfusion injury. This strategy might be successful in minimizing the side effects of current antiplatelet therapy.
Abstract
Inefficient delivery is a major obstacle to the development of peptide-based drugs targeting the intracellular compartment. We recently showed that selectively inhibiting integrin outside-in signaling using a peptide (mP6) derived from the Gα13-binding ExE motif within the integrin β3 cytoplasmic domain had antithrombotic effects. Here, we engineered lipid-stabilized, high-loading peptide nanoparticles (HLPN), in which a redesigned ExE peptide (M3mP6) constituted up to 70% of the total nanoparticle molarity, allowing efficient in vivo delivery. We observed that M3mP6 HLPN inhibited occlusive thrombosis more potently than a clopidogrel/aspirin combination without adverse effects on hemostasis in rodents. Furthermore, M3mP6 HLPN synergized with P2Y12 receptor inhibitors or the clopidogrel/aspirin combination in preventing thrombosis, without exacerbating hemorrhage. M3mP6 HLPN also inhibited intravascular coagulation more potently than the P2Y12 inhibitor cangrelor. Postischemia injection of M3mP6 HLPN protected the heart from myocardial ischemia–reperfusion injury in a mouse model. This study demonstrates an efficient in vivo peptide delivery strategy for a therapeutic that not only efficaciously prevented thrombosis with minimal bleeding risk but also protected from myocardial ischemia–reperfusion injury in mice.
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