ｐＨ勾配法によるニムスチン封入リポソームの調製と評価

Abstract

Nimustine (ACNU), one of water-soluble nitrosoureas, is used for treatment of some types of tumors. Since this drug can penetrate through the blood-brain barrier, it has been used especially for the treatment of primary brain tumors. ACNU is, however, decomposed rapidly in the blood or cerebrospinal fluid (CSF). In order to overcome this short-coming, we attempted to encapsulate ACNU in liposomes. Liposomes composed of egg phosphatidylcholine were prepared according to the procedure of the reverse-phase evaporation vesicle (REV) method. ACNU could be encapsulated efficiently into liposomes using a transmembrane pH gradient. Encapsulation efficiencies of ACNU with this method were shown to be more than 80%. The mean diameter of liposomes encapsulating ACNU (ACNU liposome) was about 300 nm. These liposomes were stable for more than 7 days at 4°C in storage. When 1 ml of ACNU solution(1 mg/ml) was added to 15 ml of artificial CSF at 37°C, concentrations of ACNU in the solution were 0.28 μg/ml at 3 hr after addition, and no ACNU was detected at 6 hr after addition. On the other hand, when 1 ml of ACNU liposome(1 mg/ml) was added to artificial CSF, concentrations of ACNU in the solution and liposomes were 6.71 and 2.62 μg/ml, respectively at 3 hr after addition. ACNU was detected at 9 hr in artificial CSF and liposomes. These results suggest that the pH gradient method is useful for encapsulation of ACNU in liposomes and the liposome formulation is useful for stabilization of ACNU in artificial CSF.