TRANSMEMBRANE AMMONIUM-SULFATE GRADIENTS IN LIPOSOMES PRODUCE EFFICIENT AND STABLE ENTRAPMENT OF AMPHIPATHIC WEAK BASES
TRANSMEMBRANE AMMONIUM-SULFATE GRADIENTS IN LIPOSOMES PRODUCE EFFICIENT AND STABLE ENTRAPMENT OF AMPHIPATHIC WEAK BASES
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DOI：
10.1016/0005-2736(93)90105-9
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发表时间：
1993-09-19
期刊：
影响因子：
--
通讯作者：
BARENHOLZ, Y
中科院分区：
文献类型：
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作者：
HARAN, G;COHEN, R;BARENHOLZ, Y
脂质体中硫酸铵的梯度[(NH4)2SO4]lip.>[(NH4)2SO4]med。用于将两亲性弱碱“主动”装载到脂质体的水室中。负载是与铵离子进行碱交换的结果。该方法用于以非常高的效率（> 90%）将蒽环类药物和吖啶橙封装在脂质体内。阿霉素在脂质体的水相中积累，其浓度达到远程加载介质中阿霉素浓度的 100 倍。大多数脂质体内阿霉素以聚集状态存在。活性包封和负载稳定性取决于脂质体脂质成分、脂质质量、培养基成分和温度，以及碱基的 pK(a) 和疏水性。硫酸铵梯度方法不同于用于远程装载脂质体的大多数其他化学方法，因为它既不需要在酸性pH下制备脂质体，也不需要碱化脂质体外水相。铵离子梯度的稳定性与其抗衡离子硫酸盐的低渗透性有关，由于蒽环类硫酸盐的聚集和胶凝，硫酸盐还可以稳定蒽环类药物在较长储存期（> 6个月）的积累。
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 pK(a) 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.