Open AccessHigh-loading Gα 13 -binding EXE peptide nanoparticles prevent thrombosis and protect mice from cardiac ischemia/reperfusion injury
Author(s) -
Aiming Pang,
Ni Cheng,
Yujie Cui,
Yanyan Bai,
Zhigang Hong,
Michael Keegan Delaney,
Yaping Zhang,
Claire Chang,
Can Wang,
Chang Liu,
Paola Leon Plata,
Alexander Zakharov,
Kasim K. Kabirov,
Jalees Rehman,
Randal A. Skidgel,
Asrar B. Malik,
Ying Li,
Aleksander V. Lyubimov,
M. Gu,
Xiaoping Du
Publication year - 2020
Publication title -
science translational medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.819
H-Index - 216
eISSN - 1946-6242
pISSN - 1946-6234
DOI - 10.1126/scitranslmed.aaz7287
Subject(s) - ischemia , reperfusion injury , medicine , thrombosis , peptide , cardiac ischemia , cardiology , pharmacology , chemistry , biochemistry
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 Gα 13 -binding ExE motif within the integrin β 3 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.