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

ACS Nano
Kalina PaunovskaJames E Dahlman

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 ...Continue Reading

References

Jan 1, 1990·Free Radical Biology & Medicine·U P SteinbrecherM Lougheed
Aug 29, 1995·Proceedings of the National Academy of Sciences of the United States of America·P K FrykmanJ Herz
Oct 28, 1998·Proceedings of the National Academy of Sciences of the United States of America·S CasesR V Farese
Oct 29, 2000·Cell·A ChawlaR M Evans
Jul 16, 2002·Arteriosclerosis, Thrombosis, and Vascular Biology·Johannes Hulthe, Björn Fagerberg
Oct 20, 2004·Circulation·Brian J O'ConnellJacques Genest
Apr 20, 2005·Lancet·Robert H EckelPaul Z Zimmet
Oct 29, 2005·Cardiovascular Research·Dayuan Li, Jawahar L Mehta
Nov 3, 2005·Nature Clinical Practice. Cardiovascular Medicine·Robin P ChoudhuryDavid R Greaves
Feb 25, 2006·The Canadian Journal of Cardiology·Hajj Hassan HassanJacques Genest
Mar 1, 2006·Nature Clinical Practice. Cardiovascular Medicine·Anatol Kontush, M John Chapman
Jan 25, 2008·Nature Reviews. Molecular Cell Biology·Elina Ikonen
Apr 29, 2008·Nature Biotechnology·Akin AkincDaniel G Anderson
Oct 6, 2009·Future Lipidology·Paul HolvoetDavid R Jacobs
Jan 19, 2010·Proceedings of the National Academy of Sciences of the United States of America·Kevin T LoveDaniel G Anderson
Jan 19, 2010·Nature Biotechnology·Sean C SempleMichael J Hope
May 13, 2010·Molecular Therapy : the Journal of the American Society of Gene Therapy·Akin AkincMartin A Maier
Sep 8, 2010·Clinica Chimica Acta; International Journal of Clinical Chemistry·Hiroshi Yoshida, Reiko Kisugi
May 3, 2011·Cell·Kathryn J Moore, Ira Tabas
Apr 6, 2012·Journal of the American Chemical Society·Delai ChenDaniel G Anderson
Dec 6, 2012·Nature Nanotechnology·Marco P MonopoliKenneth A Dawson
Jul 6, 2013·Cell·Igor Ulitsky, David P Bartel
Aug 30, 2013·The New England Journal of Medicine·Teresa CoelhoOle B Suhr
Sep 3, 2013·Nature Reviews. Immunology·Kathryn J MooreEdward A Fisher
Feb 12, 2014·Proceedings of the National Academy of Sciences of the United States of America·Yizhou DongDaniel G Anderson
May 13, 2014·Nature Nanotechnology·James E DahlmanDaniel G Anderson
Aug 13, 2014·Proceedings of the National Academy of Sciences of the United States of America·Wen XueTyler Jacks
Sep 30, 2014·Cell·Randall J PlattFeng Zhang
Oct 11, 2014·Nucleic Acids Research·Eva K BrinkmanBas van Steensel
Nov 29, 2014·Science·Jennifer A Doudna, Emmanuelle Charpentier
Jan 20, 2015·Nature Reviews. Drug Discovery·Christopher J ChengW Mark Saltzman
Jan 24, 2015·Nature Reviews. Immunology·Alan R Tall, Laurent Yvan-Charvet
Feb 11, 2015·Journal of Controlled Release : Official Journal of the Controlled Release Society·Cornelia LorenzerJohannes Winkler
Sep 9, 2015·Nature Biotechnology·Elvin BlancoMauro Ferrari
Sep 26, 2015·Arteriosclerosis, Thrombosis, and Vascular Biology·Jun-Ichiro KogaMasanori Aikawa
Jan 6, 2016·Proceedings of the National Academy of Sciences of the United States of America·Kejin ZhouDaniel J Siegwart
Feb 19, 2016·ACS Nano·Rui KuaiAnna Schwendeman

❮ Previous
Next ❯

Citations

Aug 21, 2019·Advanced Materials·Kalina PaunovskaJames E Dahlman
Aug 30, 2019·Advanced Materials·Melissa P LokugamageJames E Dahlman
Nov 20, 2019·Advanced Materials·Melissa P LokugamageJames E Dahlman
Nov 14, 2019·Cellular and Molecular Bioengineering·Cory D SagoJames E Dahlman
Oct 3, 2018·Proceedings of the National Academy of Sciences of the United States of America·Cory D SagoJames E Dahlman
Aug 4, 2020·Science Advances·Kalina PaunovskaJames E Dahlman
Sep 24, 2020·Pharmaceutics·Yanfang Wang, Ernst Wagner
Aug 18, 2020·Human Gene Therapy·Alejandro Da Silva SanchezJames E Dahlman
Feb 16, 2021·Biomaterials Science·Marco HerreraGaurav Sahay
Dec 29, 2020·Journal of Controlled Release : Official Journal of the Controlled Release Society·Yusuke SatoHideyoshi Harashima
Mar 29, 2021·Biosensors & Bioelectronics·Qing GaoBaojun Li
May 4, 2021·Chemical Reviews·Ramya KumarTheresa M Reineke
Jul 20, 2021·Chemical Reviews·Yuebao ZhangYizhou Dong
Mar 26, 2019·ACS Nano·Jonas BuckDominik Witzigmann
Nov 7, 2018·Bioconjugate Chemistry·David J PeelerSuzie H Pun
Sep 15, 2018·Nano Letters·Cory D SagoJames E Dahlman
Nov 6, 2018·Journal of the American Chemical Society·Cory D SagoJames E Dahlman
Aug 17, 2021·Nature Reviews. Materials·Xucheng HouYizhou Dong
Oct 8, 2021·Nature Biomedical Engineering·Melissa P LokugamageJames E Dahlman
Dec 4, 2021·Accounts of Chemical Research·David Loughrey, James E Dahlman

❮ Previous
Next ❯

Related Concepts

Related Feeds

ApoE, Lipids & Cholesterol

Serum cholesterol, triglycerides, apolipoprotein B (APOB)-containing lipoproteins (very low-density lipoprotein (VLDL), immediate-density lipoprotein (IDL), and low-density lipoprotein (LDL), lipoprotein A (LPA)) and the total cholesterol/high-density lipoprotein (HDL) cholesterol ratio are all connected in diseases. Here is the latest research.