Pluronic Block Copolymers Inhibit Low Density Lipoprotein Self‐Association

Abstract

Little is known about exogenous inhibitors of low-density lipoprotein (LDL) aggregation. The search for nontoxic and bioavailable inhibitors of LDL aggregation is of interest, especially considering that the suppression of the aggregation of LDL might represent a therapeutic approach. We hypothesized that amphiphilic copolymers of propylene oxide and ethylene oxide, the so-called Pluronic block copolymers, can be used to influence the aggregation of LDL. In this work we used Pluronic® P85, L61 and F68. A comparative study of the effects of Pluronic block copolymers with various hydrophilic-lipophilic properties on the aggregation process of LDL showed that Pluronic copolymers with strong hydrophobic properties (P85 and L61) at concentrations close to or greater than the respective critical concentration of micelle formation inhibited the aggregation process of LDL; however, the "hydrophilic" Pluronic F68 had no effect on the aggregation of LDL at any concentration. Thus, the study demonstrated for the first time that Pluronic® block copolymers inhibit LDL self-association. The possibility of modulating the aggregation of LDL by various Pluronic copolymers can be regarded as a prerequisite in the creation of new types of anti-atherosclerotic drugs.

Aggregation and fusion of low-density lipoproteins in vivo and in vitro

“…To this end, pluronic block copolymers were tested for their ability to prevent LDL aggregation and fusion (111). These polymers are nanomaterials consisting of hydrophilic poly-(ethylene oxide) and hydrophobic poly-(propylene oxide) blocks arranged in A-B-A tri-block structure.…”

“…These polymers can incorporate into cell membranes and translocate in the cells where they affect various cellular functions (112). A series of pluronic copolymers was tested for their ability to inhibit LDL fusion (111). LDL aggregation, which was induced by incubation at 37°C with constant stirring, was greatly diminished in a manner that was proportional to the hydrophobicity of the copolymer.…”

“…Therefore, elucidating the molecular mechanism involved in this pathogenic process and the factors that promote or prevent its specific steps may help establish new biomarkers and therapeutic targets for atherosclerosis. Analysis of lipolytic (PLA 2 , PLC, SMase) and proteolytic enzymes (trypsin, α-chymotrypsin, pronase) that promote LDL aggregation, fusion, and lipid droplet formation, as well as the amphipathic molecules (apoA-I, apoE, estradiol) and synthetic nanomaterials (pluronic copolymer) that hamper these reactions suggests that solvent exposure of hydrophobic moieties on LDL surface is a major driving force for particle aggregation and fusion (18, 33, 39, 41, 52, 110, 111). The strong effects of solvent ionic conditions (pH, monovalent and divalent cations) indicate that electrostatic interactions are also critically involved (29).…”

Anti-atherosclerotic Drugs from Natural Products

“…We have also found a positive correlation between the levels of LDL-containing immune complexes and the severity of atherosclerosis [29][30][31][32][33]. LDL is able to form complexes with collagen, elastin, and proteoglycans isolated from human aortic intima [34][35][36][37][38][39]. These LDLcontaining complexes induce intracellular cholesterol retention as a result of increased uptake and decreased intracellular degradation of lipoproteins in complexes [38].…”

Circulating desialylated low density lipoprotein

“…Further investigation of the mechanisms of LDL association revealed the factors capable to promote or prevent the association [45][46][47][48][49][50]. It turned out that the most promising are poloxamers [50][51][52]. We consider poloxamers and similar substances as candidates for antiatherosclerotic drug development.…”