Monogalactosyldiacylglycerol Confers Fusogenicity to Liposomal Delivery Systems and Facilitates Targeting to Hepatocytes

Abstract

Fusogenic liposomes typically rely on unsaturated phosphatidyleth-anolamines, usually dioleoylphosphatidylethanolamine (DOPE), to confer the ability to fuse with cell membranes and deliver drug intracellularly. Targeted fusogenic liposomes require an additional component to facilitate binding to, and internalization within, specific cell populations. This report examines the ability of the unsaturated galactolipid monogalactosyldiacylglycerol (MGDG) to replace DOPE in pH-sensitive fusogenic liposomes and to simultaneously confer enhanced binding to hepatocytes. Liposomes prepared using the pH-sensitive lipid N-succinylDOPE and either DOPE, MGDG or a non-fusogenic control galactolipid were compared for (i) propensity to undergo either pH-or calcium-induced membrane fusion; (ii) ability to deliver encapsulated gen-tamicin to infections of Salmonella typhimurium in murine macrophages; and (iii) binding and uptake into human hepatoma cells. Liposomes composed of MGDG/N-succinylDOPE were very similar to those of DOPE/N-succinyl-DOPE for both the fusion rate and final extent of fusion induced by lowered pH. In contrast, MGDG/N-succinylDOPE liposomes were substantially less susceptible than DOPE/N-succinylDOPE liposomes to fusion at physiological pH induced by addition of calcium. The ability of the MGDG/N-succinylDOPE formulation to deliver the membrane-impermeable antibiotic gentami-cin to infections of S. typhimurium in macrophages was equal or superior to that achieved by the DOPE/N-succinylDOPE preparation. The binding and uptake of MGDG/N-succinylDOPE liposomes into HepG2 hepatoma cells was 3.5-fold greater than that of the DOPE/N-succinylDOPE formulation and 7.6-fold greater than that of a galactolipid control preparation. Taken together, these data demonstrate the potential to achieve both fusogenicity and hepato-cyte targeting by the addition of a single component, MGDG, to liposomal drug delivery systems.

Keywords::

• Delivery
• Fusogenic
• Liposome
• Monogalactosyldiacylglycerol
• Targeting