An
atorvastatin calcium (AT)-loaded
dextran sulfate (DXS)-coated core-shell reconstituted
high density lipoprotein (rHDL), termed AT-DXS-LP-rHDL, was developed for targeted drug delivery to macrophages and suppression of
inflammation via the high affinity of DXS with scavenge receptor class AI (SR-AI) as well as depletion of intracellular
cholesterol by
apolipoprotein A-I (
apoA-I)-mediated
cholesterol efflux. These core-shell nanoparticles comprising an AT-loaded negatively charged
poly(lactide-co-glycolide) (PLGA) core and a cationic
lipid bilayer shell were prepared by nanoprecipitation method followed by thin film hydration and extrusion. The nanoparticles were further functionalized with
apoA-I and DXS via
sodium cholate mediation and electrostatic interaction, respectively. The core-shell structure and the surface coating of
apoA-I and DXS were verified by the increased particle size, inverted zeta potential, and reduced in vitro drug release rate. The TEM image further confirmed the entrapment of the PLGA nanoparticles in the aqueous interior of the
liposomes. In vitro cell viability assay showed the biocompatibility of the AT-loaded nanocarriers. The cellular uptake study illustrated that the targeting efficacy to macrophages increased in the following order: PLGA nanoparticles (P-NP), core-shell nanoparticles (LP-NP), core-shell rHDL (LP-rHDL), and DXS-LP-rHDL. Moreover, cellular drug efficacy of AT-loaded nanoparticles in preventing macrophage-derived foam cell formation and
inflammation such as intracellular
lipid deposition,
cholesterol esters content, DiI-
oxLDL uptake,
cholesterol efflux, and secretion of TNF-α,
IL-6, and
IL-10 was much better than that of the drug-free nanoparticles, consistent with the results of cellular uptake study. Collectively, AT-DXS-LP-rHDL, as multifunctional carriers, could not only deliver more drug to macrophages, but also present antiatherogenic actions of the biofunctional nanocarriers through damping oxidized
low density lipoproteins (
oxLDL) uptake and promoting
cholesterol efflux.