Haran G, Cohen R, Bar L K, Barenholz Y
Department of Membrane Biochemistry and Neurochemistry, Hebrew University-Hadassah Medical School, Jerusalem, Israel.
Biochim Biophys Acta. 1993 Sep 19;1151(2):201-15. doi: 10.1016/0005-2736(93)90105-9.
Gradients of ammonium sulfate in liposomes [(NH4)2SO4]lip. > [(NH4)2SO4]med. were used to obtain 'active' loading of amphipathic weak bases into the aqueous compartment of liposomes. The loading is a result of the base exchange with the ammonium ions. This approach was applied to encapsulate anthracyclines and acridine orange inside the liposomes at very high efficiency (> 90%). Doxorubicin was accumulated in the aqueous phase of the liposomes where it reached a level as high as 100-fold the doxorubicin concentration in the remote loading medium. Most of the intraliposomal doxorubicin was present in an aggregated state. The active entrapment and loading stability were dependent on liposome lipid composition, lipid quality, medium composition and temperature, as well as on the pKa and hydrophobicity of the base. The ammonium sulfate gradient approach differs from most other chemical approaches used for remote loading of liposomes, since it neither requires preparation of the liposomes in acidic pH, nor to alkalinize the extraliposomal aqueous phase. The stability of the ammonium ion gradient is related to the low permeability of its counterion, the sulfate, which also stabilizes anthracycline accumulation for prolonged storage periods (> 6 months) due to the aggregation and gelation of anthracycline sulfate salt.
利用脂质体中硫酸铵的梯度（[(NH4)2SO4]lip. > [(NH4)2SO4]med.）将两亲性弱碱“主动”载入脂质体的水相区室。这种载入是碱与铵离子进行交换的结果。该方法被用于以非常高的效率（> 90%）将蒽环类药物和吖啶橙包封在脂质体内。阿霉素在脂质体的水相中蓄积，其浓度达到远程载入介质中阿霉素浓度的100倍之高。脂质体内的阿霉素大部分以聚集状态存在。主动包封和载入稳定性取决于脂质体的脂质组成、脂质质量、介质组成和温度，以及碱的pKa和疏水性。硫酸铵梯度法与用于脂质体远程载入的大多数其他化学方法不同，因为它既不需要在酸性pH下制备脂质体，也不需要使脂质体外水相碱化。铵离子梯度的稳定性与其抗衡离子硫酸根的低渗透性有关，硫酸根还因硫酸阿霉素盐的聚集和胶凝作用而在延长的储存期（> 6个月）内稳定蒽环类药物的蓄积。
