Targeted Delivery of a Cell Membrane Repair Protein to Protect Cardiac Cells After Myocardial Infarction

Introduction:: Myocardial infarction (MI) causes extensive death of cardiac cells, leading to the decrease of cardiac function ^[1]. Quickly rescuing cardiac cells after acute MI will minimize cardiac cell loss, resulting in an improvement of cardiac function. To achieve this goal, we have developed nanoparticles that can be delivered introvensouly immediately after MI. These nanoparticles accumulate predominately in the infarcted heart, and gradally release a cell membrane repair protein, TRIM72, to repair damaged cardiac cells. Additionaly, the nanoparticles can scavenge upregulated ROS in the heart tissue, further improving cardiac cell survival.

Materials and Methods:: The effect of TRIM72 on the survival of neonatal mouse cardiomyocytes under ischemic conditions were determined. A degradable and ROS-scavenging polylmer based on N-isopropylacrylamide, acrylate-polyactide, and 4-(acryloxymethyl)-phenylboronic acid pinacol ester was synthesized by free radical polymerization. This polymer was used as the shell of the nanoparticles. The nanoparticles were fabricated using a double-emulsion method. To increase their circulation time and endow them with infarcted heart-targeting capability, the nanoparticles were cloaked with platelet membrane followed by conjugating with a cardiac targeting peptide. The targeting ability was verified by IVIS imaging. Cardiac function was monitored by echocardiography. The heart tissue was harvested 4 weeks after IV injection for histological and immunohistochemal (IHC) studies.

Results, Conclusions, and Discussions:: Results and Discussion: TRIM72 was found to increase cardiomyocyte survival under the ischemic and high ROS conditions mimicking those in the infaracted hearts (Fig. 1a). The ROS-scavenging polymer exhibited high ROS sensitivity. Its degradation rate was significantly increased under H₂O₂ (Fig. 1b). It can also efficiently scavenge hydroxyl radicals and superoxide (Fig. 1c). IVIS imaging demonstrated the nanoparticles were able to predominately accumulate in the infarcted heart tissue (Fig. 1d). The TRIM72 released from the nanoparticles significantly increased cardiomyocyte survival in the infarcted region (Fig. 1e). In addition, tissue ROS content was significantly decreased (Fig. 1f). These beneficial effects led to a significant improvement of cardiac function (Fig. 1g and h).
Conclusions: We have developed infarcted heart-targeting nanoparticles that can be delivered immediately after MI to repair damaged cardiac cells and decrease tissue ROS content. Delivery of these nanoparticles at acute MI stage significantly improved cardiac function.

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References (Optional): : [1] Sugamura, Koichi, et al., Free radical biology and medicin, 2011.