Purpose: Thymosin beta 4 (Tβ4) has multiple beneficial facets for myocardial injury, but its efficiency is limited by the low local concentration within the infarct. Here, we established a Tβ4 delivery system for cardiac repair based on the interaction between the abundant fibrin in the infarct zone and the fibrin-targeting moiety clot-binding peptide cysteine-arginine-glutamic acid-lysine-alanine (CREKA).
Methods and results: CREKA and Tβ4 were conjugated to nanoparticles (CNP-Tβ4). In vitro binding test revealed that CNP-Tβ4 had a significant binding ability to the surface of fibrin clots when compared to the control clots (NP-Tβ4). Based on the validation of fibrin expression in the early stage of ischemia injury, CNP-Tβ4 was intravenously administered to mice with acute myocardial ischemia-reperfusion injury. CNP-Tβ4 revealed a stronger fibrin-targeting ability than the NP-Tβ4 group and accumulated mainly in the infarcted area and colocalized with fibrin. Subsequently, treatment with CNP-Tβ4 resulted in a better therapeutic effect.
Conclusion: CRKEA modification favored Tβ4 accumulation and retention in the infarcted region, leading to augmented functional benefits. Fibrin-targeting delivery system represents a generalizable platform technology for regenerative medicine.
Keywords: CREKA; cardiovascular; fibrin; ischemia reperfusion; targeting delivery; thymosin beta 4.