Nanoscale Amphiphilic Macromolecules with Variable Lipophilicity and Stereochemistry Modulate Inhibition of Oxidized Low-Density Lipoprotein Uptake

Abstract

Amphiphilic macromolecules (AMs) based on carbohydrate domains functionalized with poly(ethylene glycol) can inhibit the uptake of oxidized low density lipoprotein (oxLDL) and counteract foam cell formation, a key characteristic of early atherogenesis. To investigate the influence of lipophilicity and stereochemistry on the AMs' physicochemical and biological properties, mucic acid-based AMs bearing four aliphatic chains (2a) and tartaric acid-based AMs bearing two (2b and 2l) and four aliphatic chains (2g and 2k) were synthesized and evaluated. Solution aggregation studies suggested that both the number of hydrophobic arms and the length of the hydrophobic domain impact AM micelle sizes, whereas stereochemistry impacts micelle stability. 2l, the meso analogue of 2b, elicited the highest reported oxLDL uptake inhibition values (89%), highlighting the crucial effect of stereochemistry on biological properties. This study suggests that stereochemistry plays a critical role in modulating oxLDL uptake and must be considered when designing biomaterials for potential cardiovascular therapies.

Tartaric acid-based amphiphilic macromolecules with ether linkages exhibit enhanced repression of oxidized low density lipoprotein uptake

“…As anticipated, increased inhibitory efficacy directly correlated to hydrophobic chain length for ether-linked AMs. Previous studies also found that larger and more hydrophobic sugar derivatives resulted in higher levels of oxLDL uptake inhibition [12, 30]. This result is likely due to a higher affinity binding to the hydrophobic domain of SR binding pockets.…”

“…[10, 11] Detailed studies have shown that seemingly minor changes in the stereochemistry, degree of branching, and/or hydrophobicity of the aliphatic chains have a considerable effect on bioactivity. [9, 12, 13] Molecular modeling studies further suggested that AMs competitively inhibit oxLDL uptake by SRs via electrostatic and hydrophobic interactions with SR binding domains. [14] The 3D conformation of AMs in aqueous conditions, specifically the presentation of the hydrophobic arms, appears to be critically important for this inhibition efficacy.…”

Sugar-based amphiphilic nanoparticles arrest atherosclerosis in vivo

“…AMs were synthesized as previously described (19,26,34,35) and fabricated into kinetically assembled fluorescent NPs via flash nanoprecipitation (16,17). NP shell structures are depicted in Fig.…”

Micellar and structural stability of nanoscale amphiphilic polymers: Implications for anti-atherosclerotic bioactivity

“…M12P5, T12P5-meso, and T12P5-(L) were prepared as previously published [18, 27]. The synthetic scheme of T(12-O)P5 has been reported previously; however, extremely low yield (~10%) for the alkylation step using dibenzyl L-tartrate has limited its further investigation and evaluation as an atherosclerotic therapeutic [14].…”

“…Amphiphilic polymers M12P5 [18], T12P5-meso [27], and T12P5-(L) [27] were prepared as previously published and discussed. These AMP systems are referred to as M12P5 or T12P5, in which M and T denotes mucic acid and tartaric acid, respectively, 12 refers to the number of carbon atoms of each aliphatic chain, P stands for PEG, and 5 indicates molecular weight of the PEG in kDa.…”