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- W4387253124 abstract "Cardiovascular disease remains a leading cause of global morbidity and mortality. Nanotechnology offers a unique approach to treat atherosclerosis by targeting therapeutics to sites of interest, thereby avoiding side effects from systemic administration. A liver X receptor (LXR) α agonist, GW3965, was modified to create a drug-peptide conjugate (GW3965-V 2 A 2 E 2 ) and co-assembled with a peptide amphiphile (PA) nanofiber displaying an apolipoprotein A1 (ApoA1)-mimetic sequence to target atherosclerotic plaque. A range of molar equivalents of GW3965-V 2 A 2 E 2 was co-assembled with the ApoA1-targeted PA nanofibers to investigate secondary structure motifs and supramolecular structure, with 0.5 molar equivalents showing optimal therapeutic loading. Further in vitro testing demonstrated up to 92% release of GW3965-V 2 A 2 E 2 from the nanofibers as quantified by mass spectrometry, and a critical aggregation concentration of <0.1μM for the ApoA1-GW3965 nanofibers. After 4 weeks of tail vein injections (twice/week) in low-density lipoprotein receptor knockout mice, atherosclerotic plaque size was significantly reduced by ApoA1-GW3965 nanofiber compared to controls (14% vs. 17%, p ≤ 0.01). Furthermore, we observed sex differences in the development of atherosclerosis. Male mice in the control group had greater plaque size compared to females (18.5% vs. 15.1%, p ≤ 0.02). Importantly, there was a reduction in plaque size in male mice treated with ApoA1-GW3965 nanofibers compared to male controls (13.2% vs. 18.5%, p ≤ 0.0001), whereas female mice across treatment groups demonstrated no significant change. Mice treated with ApoA1-GW3965 nanofibers showed no difference in hepatosteatosis compared to controls (34.7% vs. 36.9%, p = 0.13) and equivalent liver enzymes (AST, ALT, and ALP, p = not significant), suggestive of less hepatocyte injury in mice given the LXR agonist. In conclusion, these data demonstrate the development of an ApoA1-targeted nanotherapeutic using non-covalent incorporation of a drug-peptide conjugate with therapeutic efficacy in atherosclerotic plaque reduction. Given the known hepatotoxicity when LXR agonists are administered systemically, this work shows great promise for the targeted delivery of GW3965 for plaque reduction." @default.
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- W4387253124 date "2023-05-01" @default.
- W4387253124 modified "2023-10-03" @default.
- W4387253124 title "Abstract 127: A Targeted Nanofiber Loaded With Liver X Receptor Agonist Reduces Atherosclerotic Plaque And Prevents Hepatotoxicity" @default.
- W4387253124 doi "https://doi.org/10.1161/atvb.43.suppl_1.127" @default.
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