## 4 Discussion
One of naringenin's drawbacks is its hydrophobicity, which limits its bioavailability. However, this can be easily overcome by encapsulating it in a micelle. Our naringenin-loaded micelle had a comparable size and charge, as well as drug loading and encapsulation efficiencies compared to other PEG-based drug-loaded micelles that have been successfully used in the post-MI setting [24; 25]. The use of a micelle nanocarrier offers the potential for modifications that increase the micelle's affinity for cardiac cell-specific targets, thereby enabling higher concentrations of naringenin to be delivered to the myocardium and reducing off-target effects [20; 23]. Our study showed no renal or hepatic toxicity of naringenin when administered intra-myocardially, but future studies will be needed to investigate naringenin's efficacy and safety when administered systemically. These studies should define the in vivo release kinetics of naringenin from PEG-PCL micelles to better inform optimal dosing schedules. Suppressors of tubulin dyrovination, like naringenin, are novel indropes that may lack the drawbacks of existing treatments for cardiogenic shock. The most used indropes in clinical practice--epinephrine, dobutamine, and milrinone--work via beta-adrenergic agonism and phosphodiesterase-3 inhibition, mechanisms that augment contractility by increasing intracellular cAMP and calcium concentrations [6; 7]. This shared pathway requires adenosine triphosphate (ATP) utilization and results in increased myocardial oxygen consumption, induced myocardial ischemia, and predisposition to arrhythmias [8; 9; 10; 11]. Tubulin dyrovination suppressors alter the cytoskeletal architecture of cardiomyocytes so that they may contract and relax more efficiently without utilizing more ATP or increasing intracellular calcium or cAMP concentrations [20]. Future studies are needed to investigate whether suppressors of tubulin dyrovination are less likely to induce myocardial ischemia or arrhythmias than traditional indropes due to this unique mechanism. Additionally, future work should investigate whether the repeated use of tubulin dyrovination suppressors results in tachyphylaxis, as tachyphylaxis currently limits the use of long-term indropes. Naringenin and other tubulin dyrovinating therapies have the promise of supplementing existing indropes or replacing existing indropes when their adverse effects are intolerable. Our study's limitations are attributable to its modest sample size, reliance on a small-animal model, and assessment of a single dose and administration route of the chief therapy. Additionally, our study does not investigate the pleiotropic effects of naringenin that may have contributed to improvements in ejection fraction and myocyte contractility, such as its known antioxidant and anti-inflammatory effects in the setting of myocardial ischemia [22]. Lastly, our study did not assess whether the effects of micellized naringenin are dose-dependent or affected by the timing of administration with respect to MI. Future studies should clarify the pharmacodynamics and pharmacokinetics of micellized naringenin,characterize the impact of naringenin's pleiotropic effects on cardiomyocyteocyte contractility and hemodynamics, and assess the efficacy of repeated treatments of naringenin at multiple time points after MI.