A shuttle/sink model composing of β-cyclodextrin and simvastatin-loaded discoidal reconstituted high-density lipoprotein for enhanced cholesterol efflux and drug uptake in macrophage/foam cells
Targeting drug delivery to macrophage/foam cells is challenged by poor cell permeability and fluidity resulted from the massive accumulation of intracellular cholesterol in atherosclerosis (AS). Discoidal reconstituted high-density lipoprotein (d-rHDL) has been well regarded as a potential drug delivery system for AS by virtue of its plaque-targeting and cholesterol removal abilities, while the latter is compromised by high activation energy of cholesterol efflux. It is reported that low concentration of β-cyclodextrin (β-CD) can function as cholesterol shuttle to promote cholesterol efflux from cells to extracellular acceptors (cholesterol sink such as HDL particle), but it’s still unknown whether combination of β-CD with drug-loaded d-rHDL can function as shuttle/sink model to promote the remodeling and drug release of d-rHDL carrier after accelerating cholesterol efflux. Furthermore, it’s interesting to investigate whether enhanced cholesterol efflux can improve cellular drug uptake by restoring permeability and fluidity of cell membrane. Here, simvastatin-loaded d-rHDL (ST-d-rHDL) was combined with different concentrations of β-CD. Compared with ST-d-rHDL alone, the cholesterol removal ability of ST-d-rHDL combining with 0.5 mM of β-CD increased by 31-fold after incubation for 6 h and the cumulative drug release of ST-d-rHDL increased by 2-fold during the initial 1 h in acellular mimetic system. In macrophage/foam cells, 0.5 mM of β-CD showed better promoting effects on the cholesterol removal ability and remodeling of ST-d-rHDL than 0.1 mM of β-CD. While high concentration of β-CD at 2 mM displayed low efficiency in accelerating cholesterol efflux, which might function as cholesterol sink rather than cholesterol shuttle. Moreover, the permeability and fluidity of the cell membrane were improved by combining 0.5 mM of β-CD with ST-d-rHDL, which exhibited enhanced cellular drug uptake and inhibiting effect on intracellular lipid deposition and secretion of inflammatory cytokine. Collectively, combination of β-CD and ST-d-rHDL as shuttle/sink model could enhance cholesterol efflux and drug uptake for suppressing inflammation in macrophage/foam cells.