Elimination of liposomes by different separation principles used in low-density lipoprotein apheresis.
Clinical success of many therapies is impaired by dose limiting toxicities. Nanoscale particle-based drug delivery systems such as liposomes show unique pharmacokinetic properties and improved toxicity profiles. Liposomes accumulate in tumor tissue, but only a small fraction of a total dose reaches the target site. The overwhelming amount of a given dose is needed only to build up a diffusion gradient for effective accumulation at the target site. In order to find a way to detoxify this predominant fraction after accumulation is completed, the different separation principles used for the apheresis of lipoproteins were evaluated for the extracorporeal elimination of liposomes. Appropriate radiolabeled model liposomes were prepared by extrusion. Separation efficacy, leakage of liposomal content and influence of plasma contact were measured. Membranes with pore sizes between 25 and 400 nm were used to investigate filtration properties of liposomes. Liposomes were precipitated by adding heparin and Ca(2+). Adsorption chromatography was investigated using dextran sulfate, heparin sepharose and functionalized polyacrylamide beads. Membrane filtration allowed the elimination of various liposomes, while precipitation and adsorption were only useful for positively charged liposomes. Leakage of liposomal content was not induced by adsorption, but precipitation induced leakage. Leakage during filtration was dependent on liposomal membrane lipids. Plasma contact reduced precipitation and adsorption efficacy of positively charged liposomes, while filtration properties of liposomes remained unchanged. For extracorporeal elimination of liposomal drug delivery systems, filtration-based techniques are presumably more convenient and versatile than precipitation- or adsorption-based apheresis technologies.
Pütz
Gerhard
G
Department of Clinical Chemistry, University Medical Center Freiburg, Freiburg, Germany. puetz@medizin.ukl.uni-freiburg.de
Eckes
Jürgen
J
Schmah
Oliver
O
Winkler
Karl
K
Wieland
Heinrich
H
D000327:Adsorption; D000970:Antineoplastic Agents / Q000008:administration & dosage; D001781:Blood Component Removal / Q000379:methods*; D002118:Calcium / Q000494:pharmacology; D011232:Chemical Precipitation; D008078:Cholesterol, LDL / Q000378:metabolism*; D002845:Chromatography; D016503:Drug Delivery Systems; D006493:Heparin / Q000494:pharmacology; D006801:Humans; D008081:Liposomes / Q000493:pharmacokinetics* / Q000633:toxicity; D008567:Membranes, Artificial; D009369:Neoplasms / Q000188:drug therapy; D010949:Plasma / Q000378:metabolism*
D000970:Antineoplastic Agents; D008078:Cholesterol, LDL; D008081:Liposomes; D008567:Membranes, Artificial; D006493:Heparin; D002118:Calcium