title: Plaque-hyaluronidase-responsive high-density-lipoprotein-mimetic nanoparticles for multistage intimal-macrophage-targeted drug delivery and enhanced anti-atherosclerotic therapy.
abstract: Increasing evidence has highlighted the pivotal role that intimal macrophage (iMΦ) plays in the pathophysiology of atherosclerotic plaques, which represents an attractive target for atherosclerosis treatment. In this work, to address the insufficient specificity of conventional reconstituted high-density lipoprotein (rHDL) for iMΦ and its limited cholesterol efflux ability, we designed a hyaluronan (HA)-anchored core-shell rHDL. This nanoparticle achieved efficient iMΦ-targeted drug delivery via a multistage-targeting approach, and excellent cellular cholesterol removal. It contained a biodegradable poly (lactic-co-glycolic acid) (PLGA) core within a lipid bilayer, and apolipoprotein A-I (apoA-I) absorbing on the lipid bilayer was covalently decorated with HA. The covalent HA coating with superior stability and greater shielding was favorable for not only minimizing the liver uptake but also facilitating the accumulation of nanoparticles at leaky endothelium overexpressing CD44 receptors in atherosclerotic plaques. The ultimate iMΦ homing was achieved via apoA-I after HA coating degraded by hyaluronidase (HAase) (abundant in atherosclerotic plaque). The multistage-targeting mechanism was revealed on the established injured endothelium-macrophage co-culture dynamic system. Upon treatment with HAase in vitro, the nanoparticle HA-(C)-PLGA-rHDL exhibited a greater cholesterol efflux capacity compared with conventional rHDL (2.43-fold). Better targeting efficiency toward iMΦ and attenuated liver accumulation were further proved by results from ex vivo imaging and iMΦ-specific fluorescence localization. Ultimately, HA-(C)-PLGA-rHDL loaded with simvastatin realized the most potent anti-atherogenic efficacies in model animals over other preparations. Thus, the HAase-responsive HDL-mimetic nanoparticle was shown in this study to be a promising nanocarrier for anti-atherogenic therapy, in the light of efficient iMΦ-targeted drug delivery and excellent function of mediating cellular cholesterol efflux.
authors.affiliation: Department of Pharmaceutics, China Pharmaceutical University, Nanjing, People's Republic of China.
authors.forename: Mengyuan
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Department of Pharmaceutics, China Pharmaceutical University, Nanjing, People's Republic of China.
authors.forename: Jianhua
authors.initials: J
authors.lastname: He
authors.affiliation: Department of Pharmaceutics, China Pharmaceutical University, Nanjing, People's Republic of China.
authors.forename: Cuiping
authors.initials: C
authors.lastname: Jiang
authors.affiliation: Department of Pharmaceutics, China Pharmaceutical University, Nanjing, People's Republic of China.
authors.forename: Wenli
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Pharmaceutics, China Pharmaceutical University, Nanjing, People's Republic of China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Pharmaceutics, China Pharmaceutical University, Nanjing, People's Republic of China.
authors.forename: Zhiyu
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Pharmaceutics, China Pharmaceutical University, Nanjing, People's Republic of China.
authors.forename: Jianping
authors.initials: J
authors.lastname: Liu
mesh_terms: D000818:Animals; D002784:Cholesterol / Q000378:metabolism; D018920:Coculture Techniques; D004195:Disease Models, Animal; D016503:Drug Delivery Systems / Q000379:methods*; D065546:Drug Liberation; D005434:Flow Cytometry; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects; D006801:Humans; D006820:Hyaluronic Acid / Q000737:chemistry; D006821:Hyaluronoglucosaminidase / Q000378:metabolism*; D019344:Lactic Acid / Q000737:chemistry; D008075:Lipoproteins, HDL / Q000378:metabolism*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D053758:Nanoparticles / Q000008:administration & dosage / Q000737:chemistry* / Q000648:ultrastructure; D010316:Particle Size; D058226:Plaque, Atherosclerotic / Q000188:drug therapy* / Q000473:pathology; D011100:Polyglycolic Acid / Q000737:chemistry; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D000067996:RAW 264.7 Cells; D011817:Rabbits; D019821:Simvastatin / Q000494:pharmacology / Q000627:therapeutic use; D055672:Static Electricity; D017539:Tunica Intima / Q000378:metabolism*
chemical_list: D008075:Lipoproteins, HDL; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D006820:Hyaluronic Acid; D002784:Cholesterol; D019821:Simvastatin; D006821:Hyaluronoglucosaminidase
keywords: HAase response; anti-atherogenic efficacies; cholesterol efflux; covalent HA coating; multistage targeting for intimal macrophage; rHDL