Robust passive and active efflux of cellular cholesterol to a designer functional mimic of high density lipoprotein

Abstract

The ability of HDL to support macrophage cholesterol efflux is an integral part of its atheroprotective action. Augmenting this ability, especially when HDL cholesterol efflux capacity from macrophages is poor, represents a promising therapeutic strategy. One approach to enhancing macrophage cholesterol efflux is infusing blood with HDL mimics. Previously, we reported the synthesis of a functional mimic of HDL (fmHDL) that consists of a gold nanoparticle template, a phospholipid bilayer, and apo A-I. In this work, we characterize the ability of fmHDL to support the well-established pathways of cellular cholesterol efflux from model cell lines and primary macrophages. fmHDL received cell cholesterol by unmediated (aqueous) and ABCG1- and scavenger receptor class B type I (SR-BI)-mediated diffusion. Furthermore, the fmHDL holoparticle accepted cholesterol and phospholipid by the ABCA1 pathway. These results demonstrate that fmHDL supports all the cholesterol efflux pathways available to native HDL and thus, represents a promising infusible therapeutic for enhancing macrophage cholesterol efflux. fmHDL accepts cholesterol from cells by all known pathways of cholesterol efflux: unmediated, ABCG1- and SR-BI-mediated diffusion, and through ABCA1.

Rational Targeting of Cellular Cholesterol in Diffuse Large B-Cell Lymphoma (DLBCL) Enabled by Functional Lipoprotein Nanoparticles: A Therapeutic Strategy Dependent on Cell of Origin

“…15 Further delineation of this mechanism, and identification of targeted therapy that enables specific disruption of cholesterol metabolism in malignant B cells and other cholesterol-dependent cancer cells, may provide important new insights and more rational cancer treatment. 16–19 …”

“…16, 18, 24, 25 HDL NPs consist of a 5nm diameter gold nanoparticle core surface-functionalized with the HDL-defining apolipoprotein A1 (apoA-I) and a phospholipid bilayer. 26, 27 HDL NPs are similar to natural, mature, spherical HDL with regard to surface composition, negative surface charge, size, and shape.…”

“…16, 24, 25 Functionally, HDL NPs mediate the efflux of free cholesterol from cells through SCARB1. 16, 19 and, owing to the core gold nanoparticle, are not an appreciable source of cholesteryl ester. 18, 19 These unique features enable HDL NPs to target SCARB1, but result in cellular cholesterol reduction when compared with natural HDLs.…”

Simultaneous delivery of anti-miR21 with doxorubicin prodrug by mimetic lipoprotein nanoparticles for synergistic effect against drug resistance in cancer cells

“…35 In comparison to native HDLs, the slightly larger HMNs were still appropriate substrates for the binding and recognition by HDL receptors on the basis of earlier studies. 32,48,49 In addition, the different ζ-potentials of HMNs might reflect the exposed NLS-Dox on the surface of nanoparticles, which was used to evaluate roughly the DMPG-coating efficiency of NLS-Dox and anti-miR21 complexes. According to the results (Figure 3B), the ζ-potential of HMNs gradually decreased when the amount of DMPG was increased, and the negatively charged surface of optimized HMNs indicated the absolute shielding of cationic NLS-Dox/anti-miR21 complexes.…”

Lipoproteins and lipoprotein mimetics for imaging and drug delivery

“…[204] These HDL nanoparticles have a similar shape, size, and composition as native mature, spherical HDLs, with ~3 copies of apoA-I per nanoparticle and an outer phospholipid layer consisting of 1,2-dipalmitoyl- sn -glyerco-3-phosphocholine (DPPC). [204, 205] Functionally, these HDL nanoparticles have been shown to engage SR-B1, as well as ABC-A1 and ABC-G1, and mediate cholesterol flux through the receptors in macrophages in vitro . [204, 205] These HDL nanoparticles were able to adsorb cholesterylated antisense DNA (chol-DNA) onto their surface, and deliver the functional nucleic acid to SR-B1 expressing cells in vitro to modify gene expression.…”