Using solution X-ray scattering to determine the high-resolution structure and morphology of PEGylated liposomal doxorubicin nanodrugs
Using solution X-ray scattering to determine the high-resolution structure and morphology of PEGylated liposomal doxorubicin nanodrugs
复制标题
DOI：
10.1016/j.bbagen.2015.09.012
复制
发表时间：
2016-01-01
影响因子：
3
通讯作者：
Raviv, U.
中科院分区：
文献类型：
--
作者：
Schilt, Y.;Berman, T.;Raviv, U.
背景：在纳米药物中，载有活性剂的聚乙二醇化纳米脂质体是非常重要的。在本文中，我们研究了聚乙二醇化纳米脂质体的结构和形态之前和之后远程loading与doxorubicin.Methods：高分辨率的结构得到了溶液X射线散射结合我们先进的分析工具。我们研究了PEG化脂质体多柔比星（PLD）产品Doxil（R）及其仿制药，其中通过硫酸铵梯度进行远程多柔比星加载，以及LC 100，一种正在开发的新型PLD，其中通过甲磺酸铵梯度进行远程加载。PLD的结构进行了比较，与无药物的纳米脂质体具有相同的composition.Results：我们确定了膜的电子密度分布的空的和加载的PLD，PEG层的厚度和密度，和脂质体内部的药物的结构。我们发现，药物形成晶体内载硫酸铵的PLD，而它有一个无定形形态载甲磺酸铵的PLD。Doxil仿制药之间药物结构参数的变化与同一产品批次之间的变化相似，表明所有这些产品在结构上相似。一般意义：本文证明，当与我们强大的分析工具相结合时，溶液X射线散射可以确定纳米医学中使用的复杂非结晶纳米颗粒分散体的高分辨率结构，从而提供对其功能的有用的物理洞察。由爱思唯尔公司出版
Background: Among nanodrugs, PEGylated nanoliposomes loaded with an active agent are of major importance. In this paper we studied the structures and morphology of PEGylated nanoliposomes before and after remote loading with doxorubicin.Methods: High-resolution structures were obtained by solution X-ray scattering combined with our advanced analysis tools. We studied the PEGylated liposomal doxorubicin (PLD) product Doxil (R), and its generics, where remote doxorubicin loading is performed by a gradient of ammonium sulfate, and LC100, a novel PLD under development, where remote loading was done by a gradient of ammonium methanesulfonate. The PLD structures were compared with drug-free nanoliposomes having identical composition.Results: We determined the membrane electron density profiles of the empty and loaded PLDs, the thickness and density of the PEG layers, and the structure of the drug inside the liposomes.Conclusions: The liposomal membranes had the same structure for both ammonium salts. We found that the drug formed crystals inside PLDs loaded by ammonium sulfate, whereas it had an amorphous morphology in the PLD loaded by ammonium methanesulfonate. The variations of the drug's structural parameters between the generics of Doxil are similar to the variations between batches of the same product, suggesting that all these products were structurally similar.General significance: This paper demonstrates that solution X-ray scattering, when combined with our powerful analysis tools, can determine the high-resolution structure of complex non-crystallized nanoparticle dispersions used in nanomedicine, thereby providing useful physical insights into their functions. Published by Elsevier B.V.