Hyaluronic acid-decorated reconstituted high density lipoprotein targeting atherosclerotic lesions

Plaque-hyaluronidase-responsive high-density-lipoprotein-mimetic nanoparticles for multistage intimal-macrophage-targeted drug delivery and enhanced anti-atherosclerotic therapy

“…10,13 Furthermore, HA-(C)-PLGA-rHDL loaded with ST (ST-HA-(C)-PLGA-rHDL) was synthesized following a modified method as described by Gan et al 33 Ten milligrams of HA was dissolved in 10 mL of water (pH 4.0) overnight to allow complete swelling, and preactivated by 1 M equivalent of coupling agents EDC and NHS for 2 h at 37°C. After the addition of activated HA to ST-PLGA-rHDL solution (1:2, v:v), the reaction continued under stirring for 18 h at 25°C, and the resulting ST-HA-(C)-PLGA-rHDL was separated from free HA and residual reagents by centrifugation (13,000 rpm) for 30 min at 4°C.…”

“…Additionally, ST-loaded s-rHDL (ST-s-rHDL) and ST-HA-(E)-PLGA-rHDL formed by the electrostatic absorption between HA and cationic ST-PLGA-rHDL were obtained according to the same methods reported in our previous study, respectively. 10,13 PLGA nanoparticles loaded with ST (ST-PN) was also prepared according to a modified nanoprecipitation technique reported by Zhu et al 34 In vitro characterizations Mean size, zeta potential, ee, and Dl…”

“…Atherosclerotic NZW rabbit model was established through combining endothelial injury and high-fat diets according to the method developed in our previous studies. 13,17 In vivo atherosclerotic iMΦ-targeting property ex vivo imaging For ex vivo fluorescence imaging, near-infrared fluorescent dye DiR-loaded formulations (DiR-PLN, DiR-s-rHDL, DiR-PLGA-rHDL, DiR-HA-(E)-PLGA-rHDL, and DiR-HA-(C)-PLGA-rHDL) were prepared as described, respectively, except for the replacement of ST by DiR. Atherosclerotic NZW rabbits were respectively administrated with DiRloaded nanoparticles at a DiR dose of 0.3 mg/kg via the auris edge vein.…”

“…[10][11][12] To tackle the limited specificity of rHDL for iMΦ, electrostatic adsorption of hyaluronan (HA) on the surface of spherical rHDL (s-rHDL) had been further applied to decrease the undesired uptake by liver and improve the plaque-targeting efficiency of s-rHDL in our previous work, attributing to the weak affinity of HA for hepatic receptors, but high affinity for CD44 receptors overexpressed in the impaired endothelium of atherosclerotic plaque. [13][14][15] Nevertheless, this attempt might still be regarded as a limited success because of the following two drawbacks. On one hand, since s-rHDL consists of a lipid ester core (triglycerides and cholesteryl esters) covered with a phospholipid monolayer, its RCT function that accelerates lipid removal from iMΦ would be disappointing, due to its high cholesterol concentration of lipid core and insufficient space of phospholipid monolayer for accepting peripheral cholesterol.…”

“…11 Binding the anionic HA chains with rHDL only via electrostatic interaction is far from completely masking the negatively charged apoA-I due to the like-charge repulsion, and the unsheltered apoA-I still causes a non-ignorable amount of uptake by liver. 13 Moreover, the physical HA coating might be abscised easily under the force of disturbed flow (d-flow) in the athero-prone area. 21 Recent studies revealed that HDL-mediated cholesterol efflux in RCT primarily depends on the interaction between apoA-I and SR-BI or other efflux membrane proteins, but not on the core type of rHDL.…”