Sustained Release of a Peptide-Based Matrix Metalloproteinase-2 Inhibitor to Attenuate Adverse Cardiac Remodeling and Improve Cardiac Function Following Myocardial Infarction

Abstract

Following myocardial infarction (MI), degradation of extracellular matrix (ECM) by upregulated matrix metalloproteinases (MMPs) especially MMP-2 decreases tissue mechanical properties, leading to cardiac function deterioration. Attenuation of cardiac ECM degradation at the early stage of MI has the potential to preserve tissue mechanical properties, resulting in cardiac function increase. Yet the strategy for efficiently preventing cardiac ECM degradation remains to be established. Current preclinical approaches have shown limited efficacy due to low drug dosage allocated to the heart tissue, dose-limiting side effects, and cardiac fibrosis. To address these limitations, we have developed a MMP-2 inhibitor delivery system that can be specifically delivered into infarcted hearts at early stage of MI to efficiently prevent MMP-2-mediated ECM degradation. The system was based on an injectable, degradable, fast gelation and thermosensitive hydrogel, and a MMP-2 specific inhibitor, peptide CTTHWGFTLC (CTT). The use of fast gelation hydrogel allowed to completely retain CTT in the heart tissue. The system was able to release low molecular weight CTT over 4 weeks possibly due to the strong hydrogen bonding between the hydrogel and CTT. The release kinetics was modulated by amount of CTT loaded into the hydrogel, and using chondroitin sulfate and heparin that can interact with CTT and the hydrogel. Both glycosaminoglycans augmented CTT release while heparin more greatly accelerated the release. After injecting into the infarcted hearts for 4 weeks, the released CTT efficiently prevented cardiac ECM degradation as it not only increased tissue thickness, but also preserved collagen composition similar to that in the normal heart tissue. In addition, the delivery system significantly improved cardiac function. Importantly, the delivery system did not induce cardiac fibrosis. These results demonstrate that the developed MMP-2 inhibitor delivery system has potential to efficiently reduce adverse myocardial remodeling and improve cardiac function.

Injectable Hydrogels for Cardiac Tissue Engineering

“…Upon injection of the 10% hydrogels into a MI rat model, they found that, at 10 weeks postinjection, pathogenic ventricular remodeling was attenuated in these rats (compared to controls). In another experiment, Fan et al demonstrated that a thermosensitive PNIPAAm– co –HEMA– co –AOLA hydrogel loaded with a MMP‐2 inhibitor displayed a stiffness of 35 kPa when produced using a high concentration of PNIPAAm– co –HEMA– co –AOLA (20% w/v). This relatively stiff system efficiently prevented cardiac ECM degradation in a MI rat model and improved cardiac function.…”

Thermosensitive, fast gelling, photoluminescent, highly flexible, and degradable hydrogels for stem cell delivery

“…This is especially true for heart injection as the beating heart muscle squeezes out the injected delivery medium. Quick increase of viscosity of the delivery medium upon injection by fast gelation represents one of the strategies to increase cell retention [47, 51, 68]. Figure 8B demonstrates that the developed hydrogel significantly increased MSC retention in the muscles compared to slow gelling collagen, and non-gelling PBS.…”

“…However, the hydrogels will be injected into the infarcted region where electrical conductivity is very low. In addition, it is unclear how much disruption of electrical conductivity will cause heart tissue arrhythmias [47, 51, 68]. Previous studies using hydrogels with relatively fast gelation rate did not experience obvious arrhythmias.…”

“…AOLA was synthesized by acylation of oligolactide HO-PLA-OCH 3 with acryloyl chloride. [46, 47] To synthesize HO-PLA-OCH 3 , D,L-lactide and NaOCH3 were dissolved in CH 2 Cl 2 and methanol, respectively. The two solutions were then mixed and stirred for 2 h at 0 °C, followed by rinsing with 0.1 M HCl and deionized water [47].…”

“…[46, 47] To synthesize HO-PLA-OCH 3 , D,L-lactide and NaOCH3 were dissolved in CH 2 Cl 2 and methanol, respectively. The two solutions were then mixed and stirred for 2 h at 0 °C, followed by rinsing with 0.1 M HCl and deionized water [47]. The four components NIPAAm, HEMA, AOLA, and VP were dissolved in 1,4-dioxane in a 250 mL three-necked flask with gas inlet and outlet.…”