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ACS Nano. 2018 Aug 28;12(8):8341-8349. doi: 10.1021/acsnano.8b03640. Epub 2018 Jul 20.

Analyzing 2000 in Vivo Drug Delivery Data Points Reveals Cholesterol Structure Impacts Nanoparticle Delivery.

Author information

1
Wallace H. Coulter Department of Biomedical Engineering , Georgia Institute of Technology and Emory School of Medicine , Atlanta , Georgia 30332 , United States.
2
Petit Institute for Bioengineering and Bioscience , Georgia Institute of Technology , Atlanta , Georgia 30332 , United States.

Abstract

Lipid nanoparticles (LNPs) are formulated using unmodified cholesterol. However, cholesterol is naturally esterified and oxidized in vivo, and these cholesterol variants are differentially trafficked in vivo via lipoproteins including LDL and VLDL. We hypothesized that incorporating the same cholesterol variants into LNPs-which can be structurally similar to LDL and VLDL-would alter nanoparticle targeting in vivo. To test this hypothesis, we quantified how >100 LNPs made with six cholesterol variants delivered DNA barcodes to 18 cell types in wild-type, LDLR-/-, and VLDLR-/- mice that were both age-matched and female. By analyzing ∼2000 in vivo drug delivery data points, we found that LNPs formulated with esterified cholesterol delivered nucleic acids more efficiently than LNPs formulated with regular or oxidized cholesterol when compared across all tested cell types in the mouse. We also identified an LNP containing cholesteryl oleate that efficiently delivered siRNA and sgRNA to liver endothelial cells in vivo. Delivery was as-or more-efficient as the same LNP made with unmodified cholesterol. Moreover, delivery to liver endothelial cells was 3 times more efficient than delivery to hepatocytes, distinguishing this oleate LNP from hepatocyte-targeting LNPs. RNA delivery can be improved by rationally selecting cholesterol variants, allowing optimization of nanoparticle targeting.

KEYWORDS:

DNA barcoded nanoparticles; cholesterol structure; cholesterol trafficking; drug delivery; gene editing; nanotechnology; siRNA

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