Abstract
A liposome formulation study was performed to prepare a sustained release system of the cationic amphiphilic antitumor agent, N'-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-N-(2-chloroethyl)-N-nitrosourea hydrochloride (ACNU). Liposomes were prepared with dipalmitoylphosphatidylcholine as the main lipid component with addition of dipalmitoylphosphatidylglycerol (DPPG) and/or cholesterol, and then extruded for size control. The ACNU-loaded liposomes could be stably dispersed provided cholesterol was formulated as one of the lipid components. The dependence of the encapsulation efficiency on the kind of lipids, and concentration of either ACNU or other additional electrolytes was investigated to obtain information on the mode of encapsulation. The encapsulation efficiency was much higher than the calculated captured volume ratio within the liposomes regardless of presence or absence of DPPG, an anionic lipid, but not strongly affected by the ratio of ACNU/DPPG in feed. These results indicated that ACNU was mainly embedded inside the lipid bilayer according to its partition between the lipid bilayers and aqueous phase. By comparing the chemical stability of ACNU encapsulated in liposomes of different sizes, it was found that the larger the size, the higher the stability. This was consistent with the encapsulation mode speculated above. Furthermore, the larger liposomes resulted in ACNU release with a more sustained manner. It is expected that the ACNU-loaded liposome is applicable as a chemoembolization agent as well as a sustained release reservoir for intratumor, intramuscular and subcutaneous administrations.
