Engineered polymeric nanoparticles for receptor-targeted blockage of oxidized low density lipoprotein uptake and atherogenesis in macrophages.
Strategies to prevent the uptake of modified low density lipoproteins (LDLs) by immune cells, a major trigger of inflammation and atherogenesis, are challenged by complex interfacial factors governing LDL receptor-mediated uptake. We examine a new approach based on a family of "nanoblockers", which are designed to examine the role of size, charge presentation, and architecture on inhibition of highly oxidized LDL (hoxLDL) uptake in macrophages. The nanoblockers are macromolecules containing mucic acid, lauryl chloride, and poly(ethylene glycol) that self-assemble into 15-20 nm nanoparticles. We report that the micellar configuration of the macromolecules and the combined display of anionic (carboxylate) groups in the hydrophobic region of the nanoblockers caused the most effective inhibition in the uptake of hoxLDL by IC21 macrophages. The nanoblockers primarily targeted SR-A and CD36, the major scavenger receptors and modulated the "atherogenic" phenotype of cells in terms of the degree of cytokine secretion, accumulation of cholesterol, and "foam cell" formation. These studies highlight the promise of synthetically engineered nanoblockers against oxidized LDL uptake.
Chnari
Evangelia
E
Department of Biomedical Engineering, Rutgers University, Piscataway, New Jersey 08854, USA.
Nikitczuk
Jessica S
JS
Wang
Jinzhong
J
Uhrich
Kathryn E
KE
Moghe
Prabhas V
PV
D001161:Arteriosclerosis / Q000378:metabolism / Q000517:prevention & control*; D018955:CD36 Antigens / Q000737:chemistry / Q000187:drug effects; D002460:Cell Line; D002478:Cells, Cultured; D002784:Cholesterol / Q000737:chemistry / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D006801:Humans; D008077:Lipoproteins, LDL / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000378:metabolism*; D008823:Micelles; D015394:Molecular Structure; D049329:Nanostructures / Q000737:chemistry*; D010084:Oxidation-Reduction; D011108:Polymers / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics*; D018077:Receptors, Leukotriene / Q000737:chemistry / Q000187:drug effects*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D018955:CD36 Antigens; D008077:Lipoproteins, LDL; D008823:Micelles; D011108:Polymers; D018077:Receptors, Leukotriene; D014409:Tumor Necrosis Factor-alpha; C099252:oxidized low density lipoprotein; D002784:Cholesterol