Characterization of Stealth Liposome-Based Nanoparticles Encapsulating the ACAT1/SOAT1 Inhibitor F26: Efficacy and Toxicity Studies In Vitro and in Wild-Type Mice.

Publisher: MDPI Country of Publication: Switzerland NLM ID: 101092791 Publication Model: Electronic Cited Medium: Internet ISSN: 1422-0067 (Electronic) Linking ISSN: 14220067 NLM ISO Abbreviation: Int J Mol Sci Subsets: MEDLINE

Original Publication: Basel, Switzerland : MDPI, [2000-

Liposomes*/chemistry ; Nanoparticles*/chemistry ; Sterol O-Acyltransferase*/antagonists & inhibitors ; Sterol O-Acyltransferase*/metabolism; Animals ; Mice ; Acetyl-CoA C-Acetyltransferase/antagonists & inhibitors ; Acetyl-CoA C-Acetyltransferase/metabolism ; Brain/metabolism ; Brain/drug effects ; Enzyme Inhibitors/pharmacology ; Enzyme Inhibitors/chemistry ; Enzyme Inhibitors/administration & dosage ; Enzyme Inhibitors/pharmacokinetics ; Rats ; Male ; Alzheimer Disease/drug therapy ; Alzheimer Disease/metabolism

Cholesterol homeostasis is pivotal for cellular function. Acyl-coenzyme A:cholesterol acyltransferase 1 (ACAT1), also abbreviated as SOAT1, is an enzyme responsible for catalyzing the storage of excess cholesterol to cholesteryl esters. ACAT1 is an emerging target to treat diverse diseases including atherosclerosis, cancer, and neurodegenerative diseases. F12511 is a high-affinity ACAT1 inhibitor. Previously, we developed a stealth liposome-based nanoparticle to encapsulate F12511 to enhance its delivery to the brain and showed its efficacy in treating a mouse model for Alzheimer's disease (AD). In this study, we introduce F26, a close derivative of F12511 metabolite in rats. F26 was encapsulated in the same DSPE-PEG 2000 /phosphatidylcholine (PC) liposome-based nanoparticle system. We employed various in vitro and in vivo methodologies to assess F26's efficacy and toxicity compared to F12511. The results demonstrate that F26 is more effective and durable than F12511 in inhibiting ACAT1, in both mouse embryonic fibroblasts (MEFs), and in multiple mouse tissues including the brain tissues, without exhibiting any overt systemic or neurotoxic effects. This study demonstrates the superior pharmacokinetic and safety profile of F26 in wild-type mice, and suggests its therapeutic potential against various neurodegenerative diseases including AD.

Dis Model Mech. 2012 Nov;5(6):746-55. (PMID: 23065638)
J Lipid Res. 2000 Dec;41(12):1991-2001. (PMID: 11108732)
Neuron. 2020 Mar 4;105(5):837-854.e9. (PMID: 31902528)
Int J Mol Sci. 2024 Apr 11;25(8):. (PMID: 38673803)
J Biol Chem. 1998 Oct 9;273(41):26765-71. (PMID: 9756920)
Biomaterials. 2015 Jan;38:97-107. (PMID: 25453977)
Nat Rev Mol Cell Biol. 2020 Apr;21(4):225-245. (PMID: 31848472)
JAMA. 2009 Mar 18;301(11):1131-9. (PMID: 19293413)
Atherosclerosis. 2001 Mar;155(1):131-42. (PMID: 11223434)
Toxicol Pathol. 2011 Jan;39(1):22-35. (PMID: 21119051)
Int J Mol Sci. 2021 Oct 28;22(21):. (PMID: 34769082)
Int J Mol Sci. 2023 Mar 14;24(6):. (PMID: 36982602)
Neurotherapeutics. 2023 Jul;20(4):1120-1137. (PMID: 37157042)
J Cell Sci. 1994 Mar;107 ( Pt 3):719-26. (PMID: 8006085)
Ir J Med Sci. 2022 Aug;191(4):1549-1554. (PMID: 34460058)
Small. 2024 Aug;20(31):e2311670. (PMID: 38461531)
Biochem Pharmacol. 2001 Feb 15;61(4):387-98. (PMID: 11226372)
Biochemistry. 1986 Apr 8;25(7):1693-9. (PMID: 3707902)
Signal Transduct Target Ther. 2022 Aug 2;7(1):265. (PMID: 35918332)
J Mol Cell Biol. 2013 Dec;5(6):404-15. (PMID: 24163426)
Exp Neurobiol. 2019 Oct 31;28(5):554-567. (PMID: 31698548)
Drug Deliv Transl Res. 2013 Dec;3(6):. (PMID: 24363979)
Front Oncol. 2024 Apr 24;14:1395192. (PMID: 38720812)
Biochem J. 2005 Oct 15;391(Pt 2):389-97. (PMID: 15992359)
Future Med Chem. 2015;7(18):2451-67. (PMID: 26669800)
Biochem Pharmacol. 2001 Jan 1;61(1):97-108. (PMID: 11137714)
J Clin Invest. 2002 Oct;110(7):905-11. (PMID: 12370266)
Am J Pathol. 2000 Jan;156(1):227-36. (PMID: 10623671)
N Engl J Med. 2006 Mar 23;354(12):1253-63. (PMID: 16554527)
J Biol Chem. 1993 Oct 5;268(28):20747-55. (PMID: 8407899)
Ann Oncol. 2000 Aug;11(8):1029-33. (PMID: 11038041)
Prog Med Chem. 2002;39:121-71. (PMID: 12536672)
Proc Natl Acad Sci U S A. 2022 May 3;119(18):e2201646119. (PMID: 35507892)
Arterioscler Thromb Vasc Biol. 2006 Aug;26(8):1684-6. (PMID: 16857957)
Neuron. 2004 Oct 14;44(2):227-38. (PMID: 15473963)
J Biol Chem. 1998 Oct 9;273(41):26747-54. (PMID: 9756918)
Cell Stem Cell. 2019 Mar 7;24(3):363-375.e9. (PMID: 30686764)
Front Pharmacol. 2014 Apr 25;5:77. (PMID: 24795633)
Clin Cancer Res. 2016 Nov 1;22(21):5337-5348. (PMID: 27281560)
J Biol Chem. 1998 Oct 9;273(41):26755-64. (PMID: 9756919)
Colloids Surf B Biointerfaces. 2000 Oct 1;18(3-4):301-313. (PMID: 10915952)
Rapid Commun Mass Spectrom. 2005;19(3):297-302. (PMID: 15645487)
J Neurosci Methods. 2022 Feb 01;367:109437. (PMID: 34890698)
Int J Nanomedicine. 2006;1(3):297-315. (PMID: 17717971)
Nat Cell Biol. 2017 Jul;19(7):808-819. (PMID: 28604676)
Int J Mol Sci. 2023 Jan 02;24(1):. (PMID: 36614230)
Cardiovasc Ther. 2008 Spring;26(1):65-74. (PMID: 18466422)
Int J Mol Sci. 2023 Jul 02;24(13):. (PMID: 37446191)
Science. 2004 Mar 19;303(5665):1818-22. (PMID: 15031496)
J Biol Chem. 1998 Dec 25;273(52):35132-41. (PMID: 9857049)
Arterioscler Thromb Vasc Biol. 1998 Oct;18(10):1568-74. (PMID: 9763528)
Metabolites. 2021 Aug 14;11(8):. (PMID: 34436484)
Proc Natl Acad Sci U S A. 1974 Nov;71(11):4288-92. (PMID: 4373706)
Invest New Drugs. 2020 Oct;38(5):1421-1429. (PMID: 31984451)
J Appl Toxicol. 2003 Mar-Apr;23(2):81-7. (PMID: 12666151)
Molecules. 2020 Dec 01;25(23):. (PMID: 33271886)
Curr Opin Lipidol. 2001 Jun;12(3):289-96. (PMID: 11353332)
J Neurosci. 2014 Oct 22;34(43):14484-501. (PMID: 25339759)
J Mol Neurosci. 2009 Jan;37(1):6-15. (PMID: 18618086)
Atherosclerosis. 2007 Apr;191(2):290-7. (PMID: 16820149)
Adv Drug Deliv Rev. 2016 Apr 1;99(Pt A):28-51. (PMID: 26456916)
Int J Mol Sci. 2023 Mar 15;24(6):. (PMID: 36982689)
AAPS J. 2021 Oct 28;23(6):114. (PMID: 34713363)
Eur J Pharm Sci. 2024 Feb 1;193:106688. (PMID: 38171420)
J Lipid Res. 2004 Apr;45(4):686-96. (PMID: 14729857)
Biochim Biophys Acta. 2010 Aug;1801(8):960-5. (PMID: 20398792)
Methods Mol Biol. 2019;1965:7-17. (PMID: 31069665)
J Pharm Sci. 2004 Oct;93(10):2476-87. (PMID: 15349957)
Vaccines (Basel). 2021 Apr 08;9(4):. (PMID: 33918072)
Proc Natl Acad Sci U S A. 2010 Feb 16;107(7):3081-6. (PMID: 20133765)
PLoS One. 2020 Jan 24;15(1):e0228024. (PMID: 31978092)
Science. 1986 Apr 4;232(4746):34-47. (PMID: 3513311)
ACS Omega. 2019 Oct 02;4(16):16943-16955. (PMID: 31646241)
Circulation. 2004 Nov 23;110(21):3372-7. (PMID: 15533865)
J Appl Toxicol. 2007 Mar-Apr;27(2):103-15. (PMID: 17265431)
J Biol Chem. 2000 Sep 8;275(36):28083-92. (PMID: 10846185)

P20 GM113132 United States GM NIGMS NIH HHS; P30 CA023108 United States CA NCI NIH HHS; R01 AG063544 United States AG NIA NIH HHS; 5R01AG063544-04 United States GF NIH HHS

Keywords: ACAT1/SOAT1; Alzheimer’s disease; DSPE-PEG; F1251; F26; cholesterol; cholesteryl ester; nanoparticle; neurodegenerative diseases; phosphatidylcholine

0 (Liposomes)
EC 2.3.1.26 (Sterol O-Acyltransferase)
EC 2.3.1.26 (sterol O-acyltransferase 1)
EC 2.3.1.9 (Acetyl-CoA C-Acetyltransferase)
0 (Enzyme Inhibitors)
EC 2.3.1.9 (Acat1 protein, mouse)

Date Created: 20240914 Date Completed: 20240914 Latest Revision: 20241015

20241016

PMC11394700

10.3390/ijms25179151

39273099