| Objective:Protein-bound uremic toxins(PBUTs)are associated with various complications in patients with chronic kidney disease(CKD).However,current blood purification therapies provide insufficient clearance for PBUTs.Albumin dialysis shows good efficiency for eliminating PBUTs,however its clinical application has been limited by the source and costs of human albumin.The purpose of this study is to(1)develop a new nano material of dialysate which replaces albumin to improve the clearance of PBUTs and liver failure-related and protein-bound toxins;(2)functionalize liposomes to enhance the removal efficiency of specific protein-bound toxins according to the factors that affect the clearance of protein-bound toxins;(3)construct a preparation-biological evaluation system for liposomes as indirect adsorbent materialsMethods:(1)Unmodified liposomes and functionalized liposomes were prepared by the thin-film hydration method and then characterized.(2)Ultrafiltration was used to test the direct adsorption capacity of liposomes for the representative PBUTs or liver failure-related and protein-bound toxins including indoxyl sulfate(IS),p-cresol sulfate(PCS),bilirubin,bile acids,etc.(3)The removal efficiency of liposome dialysis for the above-mentioned protein-bound toxins was evaluated by rapid equilibrium dialysis(RED)and in vitro mini-dialyzer contained simulated hemodialysis experiment.(4)A hemodialysis system for rat was established to measure the serum levels of protein-bound toxins and to calculate the solute removal during hemodialysis.(5)The biosafety of the liposomes were evaluated by cell viability,hemolysis,the amount of liposomes potentially entering circulation during hemodialysis,etcResults:(1)The plain liposomes proved to impose good binding effects on the highly albumin-bound solutes such as unconjugated bilirubin and bile salts.The in vitro experiments showed that conventional dialysate supported by this nano material markedly improved the removal of unconjugated bilirubin,bile salts and indole.The in vivo haemodialysis model showed that liposome-containing dialysate led to a significant higher reduction ratio in total bilirubin and more total bile acids extracted in the dialysate in comparison with the conventional dialysate.(2)The liposomes were modified with linoleic acid(LA),and LA-modified liposome dialysis exhibited higher binding rates with certain protein bound-toxins in comparison with the unmodified plain liposomes.The results of RED experiments proved that dialysis supported by LA-liposomes enhanced the removal of IS,indole acetic acid and cholic acid in comparison with that of the plain liposomes.The combination of LA as competitive displacer and indirect adsorbent LA-liposomes achieved better clearing efficiency for 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid and unconjugated bilirubin in comparison with that of albumin dialysis.(3)Modified with three types of cationic modifiers,the cationic liposomes all exhibited good extraction ability for PBUTs.The removal efficiency by the cationic liposomes was strengthened with the increase of positive potentials.Different types of cationic liposomes exhibited varied clearing efficiency for PBUTs,colloidal stability and biological safety.The biological safety of the liposomes as indirect adsorbent could be evaluated by cell viability,hemolysis,the amount of liposomes potentially entering circulation during hemodialysis,etcConclusions:The unmodified liposomes exhibited high binding rates with the protein-bound and liver failure-related toxins,and liposome dialysis removed protein-bound solutes on the base of indirect adsorption.The plain liposomes were modified by LA or cationic modifiers,and the functionalized liposomes all demonstrated enhanced clearing efficiency for the specific protein-bound toxins.The specific characteristics of toxin removal and biosafety of the functionalized liposomes could be used in further studies of liposome-supported dialysis. |
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