title: Multifunctional Dextran Sulfate-Coated Reconstituted High Density Lipoproteins Target Macrophages and Promote Beneficial Antiatherosclerotic Mechanisms.
abstract: 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.
authors.affiliation: Department of Pharmaceutics, China Pharmaceutical University , Nanjing 210009, PR China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Department of Pharmaceutics, China Pharmaceutical University , Nanjing 210009, PR China.
authors.forename: Cuiping
authors.initials: C
authors.lastname: Jiang
authors.affiliation: Department of Pharmaceutics, China Pharmaceutical University , Nanjing 210009, PR China.
authors.forename: Jianhua
authors.initials: J
authors.lastname: He
authors.affiliation: Department of Pharmaceutics, China Pharmaceutical University , Nanjing 210009, PR China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Guo
authors.affiliation: Department of Pharmaceutics, China Pharmaceutical University , Nanjing 210009, PR China.
authors.forename: Jing
authors.initials: J
authors.lastname: Lu
authors.affiliation: Department of Pharmaceutics, China Pharmaceutical University , Nanjing 210009, PR China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Pharmaceutics, China Pharmaceutical University , Nanjing 210009, PR China.
authors.forename: Wenli
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Pharmaceutics, China Pharmaceutical University , Nanjing 210009, PR China.
authors.forename: Jianping
authors.identifier: 0000-0003-1825-7122
authors.initials: J
authors.lastname: Liu
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000188:drug therapy*; D000069059:Atorvastatin / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D001692:Biological Transport; D002784:Cholesterol / Q000378:metabolism; D016264:Dextran Sulfate / Q000737:chemistry*; D004337:Drug Carriers / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D016753:Interleukin-10 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D042541:Intracellular Space / Q000378:metabolism; D019344:Lactic Acid / Q000737:chemistry; D008075:Lipoproteins, HDL / Q000737:chemistry*; D008077:Lipoproteins, LDL / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D008958:Models, Molecular; D011100:Polyglycolic Acid / Q000737:chemistry; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011487:Protein Conformation; D000067996:RAW 264.7 Cells; D013499:Surface Properties; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D004337:Drug Carriers; D015850:Interleukin-6; D008075:Lipoproteins, HDL; D008077:Lipoproteins, LDL; D014409:Tumor Necrosis Factor-alpha; C099252:oxidized low density lipoprotein; D016753:Interleukin-10; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D016264:Dextran Sulfate; D002784:Cholesterol; D000069059:Atorvastatin