In Vitro Targeted Delivery of Simvastatin and Niacin to Macrophages Using Mannan-Grafted Magnetite Nanoparticles.

Abstract

Atherosclerosis, a leading cause of mortality worldwide, involves various subsets of macrophages that contribute to its initiation and progression. Current treatment approaches focus on systemic, long-term administration of cholesterol-lowering antioxidants such as statins and certain vitamins, which unfortunately come with prolonged side effects. To overcome these drawbacks, a mannose-containing magnetic nanoparticle (NP) is introduced as a drug delivery system to specifically target macrophages in vitro using simvastatin or niacin and a combinational therapy approach that reduces local inflammation while avoiding unwanted side effects. The synthesized NPs exhibited superparamagnetic behavior, neutrally charged thin coating with a hydrodynamic size of 77.23 ± 13.90 nm, and a metallic core ranging from 15 to 25 nm. Efficient loading of niacin (87.21%) and simvastatin (75.36%) on the NPs was achieved at respective weights of 20.13 and 5.03 (w/w). In the presence of a mannan hydrolyzing enzyme, 79.51% of simvastatin and 67.23% of niacin were released from the NPs within 90 min, with a leakage rate below 19.22%. Additionally, the coated NPs showed no destructive effect on J774A macrophages up to a concentration of 200 μg/mL. Simvastatin-loaded NPs exhibited a minimal increase in IL-6 expression. The low dosage of simvastatin decreased both IL-6 and ARG1 expressions, while niacin and combined simvastatin/niacin increased the level of ARG1 expression significantly. Toxicity evaluations on human umbilical vein endothelial cells and murine liver cells revealed that free simvastatin administration caused significant toxicity, whereas the encapsulated forms of simvastatin, niacin, and a combination of simvastatin/niacin at equivalent concentrations exhibited no significant toxicity. Hence, the controlled release of the encapsulated form of simvastatin and niacin resulted in the effective modulation of macrophage polarization. The delivery system showed suitability for targeting macrophages to atherosclerotic plaque.