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.
Subject(s)
Lipoproteins, LDL/metabolism , Sugar Acids/pharmacology , Surface-Active Agents/pharmacology , Tartrates/pharmacology , Atherosclerosis/drug therapy , Cells, Cultured , Drug Evaluation, Preclinical , Humans , Hydrophobic and Hydrophilic Interactions , Leukocytes, Mononuclear/drug effects , Leukocytes, Mononuclear/metabolism , Lipoproteins, LDL/antagonists & inhibitors , Micelles , Nanoparticles/chemistry , Particle Size , Polyethylene Glycols/chemical synthesis , Polyethylene Glycols/pharmacology , Stereoisomerism , Sugar Acids/chemical synthesis , Surface-Active Agents/chemical synthesis , Tartrates/chemical synthesisABSTRACT
Amphiphilic macromolecules (AMs) based on carbohydrate domains functionalized with poly(ethylene glycol) can inhibit the uptake of oxidized low density lipoprotein (oxLDL) mediated by scavenger receptor A (SR-A) and counteract foam cell formation, the characteristic "atherosclerotic" phenotype. A series of AMs was prepared by altering the carbohydrate chemistry to evaluate the influence of backbone architecture on the physicochemical and biological properties. Upon evaluating the degree of polymer-based inhibition of oxLDL uptake in human embryonic kidney cells expressing SR-A, two AMs (2a and 2c) were found to have the most efficacy. Molecular modeling and docking studies show that these same AMs have the most favorable binding energies and most close interactions with the molecular model of the SR-A collagen-like domain. Thus, minor changes in the AMs' architecture can significantly affect the physicochemical properties and inhibition of oxLDL uptake. These insights can be critical for designing optimal AM-based therapeutics for the management of cardiovascular disease.
Subject(s)
Atherosclerosis/metabolism , Carbohydrates/chemistry , Chemical Phenomena , Scavenger Receptors, Class A/metabolism , Surface-Active Agents/chemistry , Surface-Active Agents/metabolism , Animals , Cell Line , Humans , Hydrodynamics , Hydrophobic and Hydrophilic Interactions , Lipoproteins, LDL/metabolism , Mice , Micelles , Surface-Active Agents/chemical synthesisABSTRACT
Amphiphilic star polymers offer substantial promise for a range of drug delivery applications owing to their ability to encapsulate guest molecules. One appealing but underexplored application is transdermal drug delivery using star block copolymer reverse micelles as an alternative to the more common oral and intravenous routes. We prepared 6- and 12-arm amphiphilic star copolymers via atom transfer radical polymerization (ATRP) of sequential blocks of polar oligo (ethylene glycol)methacrylate and nonpolar lauryl methacrylate from brominated dendritic macroinitiators based on 2,2-bis(hydroxymethyl) propionic acid. These star block copolymers demonstrate the ability to encapsulate polar dyes such as rhodamine B and FITC-BSA in nonpolar media via UV/vis spectroscopic studies and exhibit substantially improved encapsulation efficiencies, relative to self-assembled "1-arm" linear block copolymer analogs. Furthermore, their transdermal carrier capabilities were demonstrated in multiple dye diffusion studies using porcine skin, verifying penetration of the carriers into the stratum corneum.
