Tartaric acid-based amphiphilic macromolecules with ether linkages exhibit enhanced repression of oxidized low density lipoprotein uptake |
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| Affiliation: | 1. Department of Chemistry and Chemical Biology, Rutgers University, NJ, USA;2. Department of Chemical and Biochemical Engineering, Rutgers University, NJ, USA;3. Department of Biomedical Engineering, Rutgers University, NJ, USA;4. Department of Pharmacology, Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, Rutgers University, Piscataway, NJ, USA;1. Department of Microbiology and Immunology, Peter Doherty Institute for Infection & Immunity, The University of Melbourne, Parkville 3010, Australia;2. Faculty of Science, Swinburne University of Technology, Hawthorn 3122, Australia;1. Department of Pharmaceutical Sciences and Center for Cancer Research, University of Tennessee Health Science Center, Memphis, TN, USA;2. Cancer Biology Research Center, Sanford Research/USD, Sioux Falls, SD, USA;3. College of Medicine, University of Tennessee Health Science Center, Memphis, TN, USA;4. Methodology and Data Analysis Center, Sanford Research, Sioux Falls, SD, USA;5. Department of Pharmaceutical Sciences and Plough Center for Sterile Drug Delivery Systems, University of Tennessee Health Science Center, Memphis, TN, USA;6. Department of Surgery, University of Tennessee Health Science Center, Memphis, TN, USA;7. Department of Pathology, University of Tennessee at Memphis, Memphis, TN, USA;8. Saraswati Dental College, Lucknow, Uttar Pradesh, India;9. Department of Chemistry & Biochemistry, South Dakota State University, Brookings, SD, 57007, USA;1. Department of Chemistry, and Advanced Research Institute, Tongji University, Shanghai 200092, China;2. Lab of Low-Dimensional Materials Chemistry, Key Laboratory for Ultrafine Materials of Ministry of Education, School of Materials Science and Engineering, East China University of Science and Technology, Shanghai 200237, China;3. Department of Radiology, Shanghai Cancer Hospital, Fudan University, Shanghai 200032, China;1. Department of Biomaterials Science and Technology, Targeted Therapeutics, MIRA Institute for Biomedical Technology and Technical Medicine, University of Twente, Enschede 7500AE, The Netherlands;2. Cristal Therapeutics, Oxfordlaan 55, Maastricht 6229EV, The Netherlands;3. Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht 3584CG, The Netherlands;4. Cancer Centre Karolinska, Karolinska Institutet, Stockholm SE-171 76, Sweden;1. InGell Labs BV, Groningen, The Netherlands;2. Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands;3. Department of Equine Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands |
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| Abstract: | Cardiovascular disease initiates with the atherogenic cascade of scavenger receptor- (SR-) mediated oxidized low-density lipoprotein (oxLDL) uptake. Resulting foam cell formation leads to lipid-rich lesions within arteries. We designed amphiphilic macromolecules (AMs) to inhibit these processes by competitively blocking oxLDL uptake via SRs, potentially arresting atherosclerotic development. In this study, we investigated the impact of replacing ester linkages with ether linkages in the AM hydrophobic domain. We hypothesized that ether linkages would impart flexibility for orientation to improve binding to SR binding pockets, enhancing anti-atherogenic activity. A series of tartaric acid-based AMs with varying hydrophobic chain lengths and conjugation chemistries were synthesized, characterized, and evaluated for bioactivity. 3-D conformations of AMs in aqueous conditions may have significant effects on anti-atherogenic potency and were simulated by molecular modeling. Notably, ether-linked AMs exhibited significantly higher levels of inhibition of oxLDL uptake than their corresponding ester analogues, indicating a dominant effect of linkage flexibility on pharmacological activity. The degradation stability was also enhanced for ether-linked AMs. These studies further suggested that alkyl chain length (i.e., relative hydrophobicity), conformation (i.e., orientation), and chemical stability play a critical role in modulating oxLDL uptake, and guide the design of innovative cardiovascular therapies. |
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| Keywords: | Amphiphilic macromolecule Atherosclerosis Self-assembled micelle oxLDL uptake |
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