Formulating Elafibranor and Obeticholic Acid in Liposomes Decreases Drug-Induced Association of SPARC to LX-2 Hepatic Stellate Cells’ Extracellular Vesicles
34 Pages Posted: 8 Aug 2022
Chronic hepatic diseases often compromise liver function and are directly responsible for up to two million yearly deaths world-wide. There are yet no treatment options to solve this global medical need.Experimental drugs elafibranor (Ela) and obeticholic acid (OA) appeared promising in numerous earlier studies, but they recently struggled to show significant benefits in patients. Little is known on the drugs’ impact on hepatic stellate cells (HSCs), key players in liver fibrogenesis. We previously reported a beneficial effect of polyenylphosphatidylcholines (PPCs)-rich formulations in reverting fibrogenic features of HSCs, including differences in their extracellular vesicles (EVs).Here, we newly formulated Ela and OA in PPC liposomes and evaluated their performance on the LX-2 (human HSC) cell line through our rigorous methods of EV-analysis, now expanded to include lipidomics. We show that direct treatments with Ela and OA increase EV-associated secreted protein acidic and cysteine rich (SPARC), a matricellular protein overexpressed in fibrogenesis. However, our results suggest that this potentially damaging drugs’ action to HSCs could be mitigated when delivering them with lipid-based nanocarriers, most notably with PPC-rich S80 liposomes inducing specific changes in the cellular and EV phospholipid composition. Thus, EV analysis substantially deepens evaluations of drug performances and delivery strategies.
Funding Information: The Phospholipid Research Center is kindly acknowledged for the financial support (Grant ID: PLU-2017-056/2-1, AKO-2019-070/2-1). G.F. would like to acknowledge financial support from the NanoMatFutur program from the Federal Ministry of Research and Education (grant number 13XP5029A).
Declaration of Interests: No private study sponsors had any involvement in study design, data collection, or interpretation of data presented in this manuscript. P.L. has consulted to Lipoid GmbH and Sanofi-Aventis Deutschland, and received research grants from Lipoid, Sanofi-Aventis Deutschland and DSM Nutritional Products Ltd. C.Z., F.W., A.K. and G.F. declare that there are no competing interests.“
Keywords: extracellular vesicles, SPARC, elafibranor, obeticholic acid, liposomes
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