Alginate and Alginate Sulfate/Polycaprolactone Nanoparticles as a Novel Drug Delivery System for the Delivery of Insulin-like Growth Factor 1 (IGF-1) in Cardiac Hypoxia/Reoxygenation

Abstract

Myocardial infarction (MI) is a condition associated with the highest mortality rates worldwide. It is caused by the rupture of plaques on the anterior coronary artery walls, leading to an intense shortage of oxygen and nutrients, resulting in cardiomyocyte death. Conventional treatments involve clot-dissolving agents and oxygen; however, MI is still linked with cardiac muscle damage and heart failure. Metabolic molecules such as insulin-like growth factor 1 (IGF-1) could provide cardioprotective effects yet, it has a short half-life which reduces its efficiency and bioavailability. Nanoparticle (NP)-based delivery systems were established to enhance bioavailability of the delivered IGF-1; however, they lacked the high growth factor affinity binding and controlled IGF-1 release. In this study, we engineered a novel IGF-1 nanocarrier made of pure alginate (PA) or growth factor affinity binding sulfated alginate (SA) polymers, combined with a synthetic polymer, polycaprolactone (PCL), to form double emulsion NPs. This delivery system was assessed in vitro on neonatal rat cardiomyocytes (NCM) after hypoxia/reoxygenation (H/R) injury. Viability and activity were assessed using trypan blue and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assays. Protein expression and synthesis were evaluated using polymerase chain reaction (PCR) and western blotting. The NPs exhibited a size range of 200 to 250 nm and a negative zeta potential range of -11 to -13.3 mV, which renders them suitable for drug delivery applications. The biocompatibility of the NPs was evident from the absence of significant cell death upon treatment of NCM with different concentrations of NPs ranging from 5 to 100 µg/mL. Additionally, without treatment, a significant 46% ± 10% decrease (P=0.01) in NCM viability was observed after H/R injury with a significant 1.65-fold ± 0.12 increase (P=0.04) in the transcription of cell survival markers. However, treatment of NCM with IGF-1 loaded PA and SA NPs post H/R, reduced the cell death profile to only 12-28% and increased the expression of pAkt cell survival signaling pathway. With the obtained promising results and further in vitro and in vivo studies, IGF-1 loaded alginate/PCL delivery system may be adopted as an MI treatment to reduce the expanding mortality rates. While the developed drug delivery system was evaluated for MI, it represents a versatile platform that can be adopted for other diseases requiring affinity binding to different growth factors.