Linoleic acid-modified liposomes for the removal of protein-bound toxins: An in vitro study

Abstract

Introduction:

Protein-bound uremic toxins (PBUTs) and liver failure-related cholestatic solutes are associated with adverse outcomes in patients with chronic kidney disease (CKD) and liver failure, respectively, and are not easily removed by traditional dialysis therapies. We constructed linoleic acid-modified liposomes (LA-liposomes) as indirect adsorbent in the dialysate, and evaluated their effects on the clearance of the representative PBUTs and cholestatic solutes.

Methods:

The LA-liposomes were prepared by the thin-film hydration method. The binding rates of liposomes and protein-bound solutes were detected by the ultrafiltration column. The in vitro dialysis experiments were performed using both non-current and current devices to assay the clearing efficiency of the dialysate supported by LA-liposomes.

Results:

The LA-liposomes exhibited good binding properties to the PBUTs, bilirubin and bile acids. The LA-liposome dialysate showed higher solute reduction rates of the representative PBUTs and cholestatic solutes than the traditional dialysate or dialysate supported by the unmodified plain liposomes. Also, albumin binding of the PBUTs was significantly inhibited by the addition of linoleic acid (LA), and the removal efficiency of PBUTs was greatly enhanced by the combination of indirect adsorbent LA-liposomes and LA as the competitive displacer.

Conclusion:

LA-liposomes were efficient in the clearance of the representative PBUTs and liver failure-related solutes. Moreover, the combination of indirect adsorbent LA-liposomes and competitive displacer suggested a potential application for the extremely highly-bound solutes.

Keywords

Liposome protein-bound uremic toxins cholestasis hemodialysis adsorbent

Get full access to this article

View all access options for this article.

References

Duranton

Cohen

De Smet

, et al. Normal and pathologic concentrations of uremic toxins. J Am Soc Nephrol 2012; 23(7): 1258–1270.

Vanholder

Schepers

Pletinck

, et al. The uremic toxicity of indoxyl sulfate and p-cresyl sulfate: a systematic review. J Am Soc Nephrol 2014; 25(9): 1897–1907.

Goncharova

Orlov

Urbanova

The location of the high- and low-affinity bilirubin-binding sites on serum albumin: ligand-competition analysis investigated by circular dichroism. Biophys Chem 2013; 180–181: 55–65.

Cordoba

Ventura-Cots

Simon-Talero

, et al. Characteristics, risk factors, and mortality of cirrhotic patients hospitalized for hepatic encephalopathy with and without acute-on-chronic liver failure (ACLF). J Hepatol 2014; 60(2): 275–281.

Bañares

Catalina

Vaquero

Molecular adsorbent recirculating system and bioartificial devices for liver failure. Clin Liver Dis 2014; 18(4): 945–956.

Niwa

Removal of protein-bound uraemic toxins by haemodialysis. Blood Purif 2013; 35(Suppl 2): 20–25.

Rifai

Extracorporeal albumin dialysis. Hepatol Res 2008; 38(Suppl 1): S41–S45.

Forster

Signorell

Roveri

, et al. Liposome-supported peritoneal dialysis for detoxification of drugs and endogenous metabolites. Sci Transl Med 2014; 6(258): 258ra141.

Shi

Wang

, et al. Increasing the removal of protein-bound uremic toxins by liposome-supported hemodialysis. Artif Organs 2019; 43(5): 490–503.

10.

Shen

Wang

Shi

, et al. Development of liposome as a novel adsorbent for artificial liver support system in liver failure. J Liposome Res 2020; 303(3): 246–254.

11.

Shi

Zhang

Tian

, et al. Improved dialytic removal of protein-bound uremic toxins by intravenous lipid emulsion in chronic kidney disease rats. Nephrol Dial Transplant 2019; 34(11): 1842–1852.

12.

Shen

Liu

Shi

, et al. Bisphenol a analogs in patients with chronic kidney disease and dialysis therapy. Ecotoxicol Environ Saf 2019; 185: 109684.

13.

Shen

Wang

Shi

, et al. Improving the clearance of protein-bound uremic toxins using cationic liposomes as an adsorbent in dialysate. Colloids Surf B Biointerfaces 2019; 186: 110725.

14.

Tao

Thijssen

Kotanko

, et al. Improved dialytic removal of protein-bound uraemic toxins with use of albumin binding competitors: an in vitro human whole blood study. Sci Rep 2016; 6: 23389.

15.

Bammens

Evenepoel

Keuleers

, et al. Free serum concentrations of the protein-bound retention solute p-cresol predict mortality in hemodialysis patients. Kidney Int 2006; 69(6): 1081–1087.

16.

Krieter

Hackl

Rodriguez

, et al. Protein-bound uraemic toxin removal in haemodialysis and post-dilution haemodiafiltration. Nephrol Dial Transplant 2010; 25(1): 212–218.

17.

Yamamoto

Ito

Sato

, et al. Adsorption of protein-bound uremic toxins using activated carbon through direct hemoperfusion in vitro. Blood Purif 2019; 48(3): 215–222.

18.

Tijink

Wester

Glorieux

, et al. Mixed matrix hollow fiber membranes for removal of protein-bound toxins from human plasma. Biomaterials 2013; 34(32): 7819–7828.

19.

Pavlenko

Giasafaki

Charalambopoulou

, et al. Carbon adsorbents with dual porosity for efficient removal of uremic toxins and cytokines from human plasma. Sci Rep 2017; 7(1): 14914.

20.

Mingrone

De Smet

Greco

, et al. Serum uremic toxins from patients with chronic renal failure displace the binding of L-tryptophan to human serum albumin. Clin Chim Acta 1997; 260(1): 27–34.

21.

Meijers

Bammens

Verbeke

, et al. A review of albumin binding in CKD. Am J Kidney Dis 2008; 51(5): 839–850.

22.

Watanabe

Noguchi

Miyamoto

, et al. Interaction between two sulfate-conjugated uremic toxins, p-cresyl sulfate and indoxyl sulfate, during binding with human serum albumin. Drug Metab Dispos 2012; 40(7): 1423–1428.

23.

Sakai

Takadate

Otagiri

Characterization of binding site of uremic toxins on human serum albumin. Biol Pharm Bull 1995; 18(12): 1755–1761.

24.

Deltombe

de Loor

Glorieux

, et al. Exploring binding characteristics and the related competition of different protein-bound uremic toxins. Biochimie 2017; 139: 20–26.

25.

Orlov

Goncharova

Urbanová

Circular dichroism study of the interaction between mutagens and bilirubin bound to different binding sites of serum albumins. Spectrochim Acta A Mol Biomol Spectrosc 2014; 126: 68–75.

26.

Zsila

Subdomain IB is the third major drug binding region of human serum albumin: toward the three-sites model. Mol Pharm 2013; 10(5): 1668–1682.

27.

Fehske

Müller

Wollert

The location of drug binding sites in human serum albumin. Biochem Pharmacol 1981; 30(7): 687–692.

28.

Brock

Binding of digitoxin to human serum albumin: influence of free fatty acids, bile acids, and protein unfolding on the digitoxin-albumin interaction. Acta Pharmacol Toxicol (Copenh) 1976; 38(5): 497–507.

29.

Zsila

Circular dichroism spectroscopic detection of ligand binding induced subdomain IB specific structural adjustment of human serum albumin. J Phys Chem B 2013; 117(37): 10798–10806.

30.

Krenzel

Chen

Hamilton

JA.

Correspondence of fatty acid and drug binding sites on human serum albumin: a two-dimensional nuclear magnetic resonance study. Biochemistry 2013; 52(9): 1559–1567.

31.

Bowmer

Donoghue

Leong

, et al. Effect of bile acids on the binding of drugs and dyes to human albumin. J Pharm Pharmacol 1985; 37(11): 812–815.

32.

Madero

Cano

Campos

, et al. Removal of protein-bound uremic toxins during hemodialysis using a binding competitor. Clin J Am Soc Nephrol 2019; 14(3): 394–402.

Supplementary Material

Please find the following supplemental material available below.

For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.

For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.

0.00 MB

0.59 MB