High ceramide content liposomes with in vivo antitumor activity.
BACKGROUND
The pro-apoptotic activity of ceramide lipids has made this an exciting new target for therapeutic manipulation. While approaches using exogenous application of short-chain ceramides and modulation of endogenous ceramide levels via manipulation of metabolic pathways have been explored, controlled delivery of natural ceramide has not been previously reported. In this paper we describe the formulation of novel liposomes containing high levels of natural ceramide in the lipid bilayer for the purpose of controlled ceramide delivery.


METHODS
Liposomes were characterized by cryo-transmission electron microscopy, quasi-elastic light scattering and trapped volume analysis. Pharmacokinetic analysis was performed following i.v. bolus dosing, and antitumor activity was evaluated following i.v. bolus and i.p. dosing in the J774 ascites tumor model.


RESULTS
Stable ceramide-containing liposomes exhibited pharmacokinetic properties suitable for in vivo applications and resulted in an increase in lifespan of greater than 20% compared to control liposomes following i.v. bolus and i.p. administration.


CONCLUSIONS
This work demonstrates proof-of-concept that delivery of exogenous natural ceramide lipid has antitumor activity in vivo, and highlights the potential utility of ceramide-based liposomes as a novel strategy for cancer chemotherapy based on controlled ceramide delivery.
Shabbits
Jennifer A
JA
Department of Advanced Therapeutics, British Columbia Cancer Research Centre, Faculty of Pharmaceutical Sciences, University of British Columbia, 2146 East Mall, Vancouver, British Columbia, V6T 1Z3, Canada.
Mayer
Lawrence D
LD
D000818:Animals; D001201:Ascites / Q000188:drug therapy / Q000378:metabolism; D045744:Cell Line, Tumor; D002518:Ceramides / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D005260:Female; D008051:Lipid Bilayers / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D008081:Liposomes / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C
D002518:Ceramides; D008051:Lipid Bilayers; D008081:Liposomes