Here we report that the size dependence of cellular internalization of liposomes differs depending on the surface charge. We prepared liposomes of various lipid compositions ranging from 100 to 200 nm size. It was found that cationic liposomes composed of 1,2-Dioleoyl-sn-glycero-3-phosphocholine (DOPC) and 1,2-Dioleoyl-3-trimethylammonium-propane (DOTAP) were most effectively internalized into cells when their mean particle sizes were around 180 nm. When their size was reduced to around 90 nm, the level of internalization reduced six-fold. Conversely, hydrogenated soy phosphatidylcholine (HSPC)/N-(carbonyl-methoxypolyethylene glycol 2000)-1,2-distearoyl-sn-glycero-3-phosphoethanolamine (PEG2000-DSPE)/cholesterol(Chol) liposomes, HSPC/PEG2000-DSPE liposomes, and HSPC/Chol liposomes were most readily internalized when they were around 110 to 130 nm in mean particle size. Unlike DOPC/DOTAP liposomes the difference between the maximum and minimum levels of internalization was less than two-fold. It has been suggested that strong electrostatic interactions between cationic liposomes and the negatively charged plasma membrane affect the size dependence and optimal size range for internalization of liposomes. Size dependence of internalization should be carefully monitored for effective formulation development and quality control of liposome drug products.
Keywords: Internalization; Lipid composition; Liposome; Size dependence; Surface charge.
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