Enhanced Antiatherosclerotic Efficacy of Statin-Loaded Reconstituted High-Density Lipoprotein via Ganglioside GM1 Modification

Atherosclerosis remains one of the leading causes of morbidity and mortality globally. Recently, reconstituted high-density lipoprotein (rHDL), the synthetic form of endogenous plasma HDL, has been utilized as a therapeutic delivery system for statins, a class of lipid-lowering drugs, to treat atherosclerosis. Accumulating evidence suggests that ganglioside GM1 modification can induce an increased stability, a prolonged circulation time, and a decreased reticuloendothelial system uptake of liposomes. Therefore, we hypothesized that GM1 modification probably has similar effects on statin-loaded rHDL and finally enhances its inhibitory effect on atherogenesis. To test this hypothesis, we prepared GM1-modified lovastatin (LT)-loaded rHDL (LT-GM1-rHDL), as well as LT-loaded rHDL (LT-rHDL) and LT-loaded nanostructured lipid carriers (LT-NLC) for comparison, via thin film dispersion followed by physicochemical characterization, in vitro LT release assay, and in vitro cellular experiments. Subsequently, the pharmacokinetic behavior, tissue distribution, and in vivo antiatherosclerotic effect of all LT-loaded nanocarriers were evaluated by using ApoE –/– mice fed with a high-fat diet. We found that LT-GM1-rHDL has a more efficient LT sustained-release, a longer circulation time, a lower liver uptake, a better atherosclerotic plaque targeting efficiency, and a stronger inhibitory effect on atherogenesis compared with LT-NLC and LT-rHDL. The data verified our hypothesis that GM1 modification of statin-loaded rHDL can induce an enhanced inhibitory effect on atherogenesis and imply that statin-GM1-rHDL can potentially be recruited as a promising drug delivery system for the treatment of atherosclerosis.