Encapsulation of doxorubicin into thermosensitive liposomes via complexation with the transition metal manganese
Encapsulation of doxorubicin into thermosensitive liposomes via complexation with the transition metal manganese
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DOI：
10.1016/j.jconrel.2005.02.009
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发表时间：
2005-05-18
影响因子：
10.8
通讯作者：
Bally, MB
中科院分区：
文献类型：
--
作者：
Chiu, GNC;Abraham, SA;Bally, MB
在本研究中，将阿霉素包封在两种热敏脂质体制剂中，所述热敏脂质体制剂由DPPC/MSPC/DSPE-PEG（2000）（90/10/4摩尔比）或DPPC/DSPE-PEG（2000）（95/5摩尔比）组成。通过使用pH梯度或涉及多柔比星与锰络合的新程序来实现多柔比星负载。无论初始药物与脂质比（D：L）如何，当多柔比星通过pH梯度包封时，两种当时不敏感的脂质体制剂的最终D：L达到最大值0.05（w/w）。相比之下，通过锰络合实现的最终最大D：L为0.2（w/w），并且这种加载方法不影响温度诱导的药物释放，在42 ° C下10分钟内从含有MSPC的脂质体释放85%的药物，但在37 ° C下60分钟内释放< 5%。当通过两种不同装载方法制备的热敏脂质体注射到小鼠体内时，观察到相似的血浆消除曲线。冷冻透射电子显微镜分析表明，阿霉素纤维束的存在下，通过pH梯度加载的脂质体相比，在那些通过锰络合加载的斑点和扩散形态。为了研究脂质体内pH对药物沉淀形态的影响，将A23187离子载体（介导Mn 2 +/H+交换）加入到负载有多柔比星-锰复合物的脂质体中，并且在脂质体核心酸化后，点画和弥散的外观可以转化为显示纤维束的外观。这表明当脂质体内pH> 6.5时，多柔比星-锰复合物的形成是有利的。在转化为纤维束形态的过程中，当A23187加入到表现出0.05（w/w）的脂质体中时，没有观察到多柔比星释放，而当初始D：L为0.2（w/w）时，注意到显著的释放。在脂质体内部酸化并建立明显的新D：L平衡后，测得的D：L比为0.05（w/w）。总之，锰络合负载方法增加了阿霉素在热敏脂质体中的包封效率，对温度触发的药物释放或药代动力学没有重大影响。(c)2005 Elsevier B. V.保留所有权利。
In the present study, doxorubicin was encapsulated into two thermosensitive liposome formulations which were composed of DPPC/MSPC/DSPE-PEG(2000) (90/10/4 mole ratio) or DPPC/DSPE-PEG(2000) (95/5 mole ratio). Doxorubicin loading was achieved through the use of a pH gradient or a novel procedure that involved doxorubicin complexation with manganese. Regardless of the initial drug-to-lipid ratios (D: L), the final D : L reached a maximum of 0.05 (w/w) when doxorubicin was encapsulated via a pH gradient for both then-no sensitive liposome formulations. In contrast, the final maximum D : L achieved through manganese complexation was 0.2 (w/w), and this loading method did not affect temperature-induced drug release, with 85% of drug released from MSPC-containing liposomes within 10 min at 42 degrees C but < 5% released over 60 min at 37 degrees C. When the thermosensitive liposomes prepared via the two different loading methods were injected into mice, similar plasma elimination profiles were observed. Cryo-transmission electron microscopy analysis indicated the presence of doxorubicin fiber bundles in liposomes loaded via pH gradient, compared to a stippled and diffuse morphology in those loaded via manganese complexation. To investigate the effect of intraliposomal pH on drug precipitate morphology, the A23187 ionophore (mediates Mn2+/H+ exchange) was added to liposomes loaded with doxorubicin-manganese complex, and the stippled and diffuse appearance could be converted to one exhibiting fiber bundles after acidification of the liposome core. This suggests that the formation of doxorubicin-manganese complex is favored when the intraliposomal pH is > 6.5. During the conversion to the fiber bundle morphology, no doxorubicin release was observed when A23187 was added to liposomes exhibiting a 0.05 (w/w), whereas a significant release was noted when the initial D: L was 0.2 (w/w). Following acidification of the liposomal interior and establishment of an apparent new D: L equilibrium, the measured D: L ratio was 0.05 (w/w). In conclusion, the manganese complexation loading method increased the encapsulation efficiency of doxorubicin in thermosensitive liposomes with no major impact on temperature-triggered drug release or pharmacokinetics. (c) 2005 Elsevier B.V. All rights reserved.