Controlled dual delivery of fibroblast growth factor-2 and Interleukin-10 by heparin-based coacervate synergistically enhances ischemic heart repair

Abstract

Myocardial infarction (MI) causes myocardial necrosis, triggers chronic inflammatory responses, and leads to pathological remodeling. Controlled delivery of a combination of angiogenic and immunoregulatory proteins may be a promising therapeutic approach for MI. We investigated the bioactivity and therapeutic potential of an injectable, heparin-based coacervate co-delivering an angiogenic factor, fibroblast growth factor-2 (FGF2), and an anti-inflammatory cytokine, Interleukin-10 (IL-10) in a spatially and temporally controlled manner. Coacervate delivery of FGF2 and IL-10 preserved their bioactivities on cardiac stromal cell proliferation in vitro. Upon intramyocardial injection into a mouse MI model, echocardiography revealed that FGF2/IL-10 coacervate treated groups showed significantly improved long-term LV contractile function and ameliorated LV dilatation. FGF2/IL-10 coacervate substantially augmented LV myocardial elasticity. Additionally, FGF2/IL-10 coacervate notably enhanced long-term revascularization, especially at the infarct area. In addition, coacervate loaded with 500 ng FGF2 and 500 ng IL-10 significantly reduced LV fibrosis, considerably preserved infarct wall thickness, and markedly inhibited chronic inflammation at the infarct area. These results indicate that FGF2/IL-10 coacervate has notably greater therapeutic potential than coacervate containing only FGF2. Overall, our data suggest therapeutically synergistic effects of FGF-2/IL-10 coacervate, particularly coacervate with FGF2 and 500 ng IL-10, for the treatment of ischemic heart disease.

A single injection of protein-loaded coacervate-gel significantly improves cardiac function post infarction

“…We have shown the efficacy of this coacervate-gel system for sequential release of VEGF and platelet-derived growth factors (PDGF) previously [11]. We have demonstrated in a number of studies the advantage of coacervate-delivered proteins for many biomedical applications, including cardiac repair [9, 11, 22–26]. The complex coacervate is comprised of a synthetic polycation PEAD combined with heparin and a heparin-binding protein, enabling its sustained release over time due to PEAD degradation, changes in ionic strength, presence of enzymes, and other factors [8, 10].…”

Decellularized zebrafish cardiac extracellular matrix induces mammalian heart regeneration

“…The induction of MI and intramyocardial injections were performed, as we previously reported ( 62 , 63 ). After MI induction, mice were randomly assigned to one of the four groups: hzECM, nzECM, mECM, or saline control.…”

“…Echocardiographic studies were performed by a blinded investigator repeatedly before surgery and at 5 days, 2 weeks, and 6 weeks after surgery, as previously described ( 63 , 64 ). Echocardiographic parameters were measured using a high-frequency linear probe (MS400, 30 MHz) connected to a high-resolution ultrasound imaging system (Vevo 2100; FUJIFILM VisualSonics).…”

Dual Delivery of bFGF- and NGF-Binding Coacervate Confers Neuroprotection by Promoting Neuronal Proliferation

“…The coacervate maintains the native properties and function of heparin through the direct, ionic interactions with PEAD [21], which not only improves GF loading efficiency and maintains their bioactivity, but also well controls the release of GFs to target tissues [20]. Thus, coacervate had been widely used to spatially and temporally control the release of GFs [22][23][24][25].…”