ATP-Responsive Liposomes via Screening of Lipid Switches Designed to Undergo Conformational Changes upon Binding Phosphorylated Metabolites
ATP-Responsive Liposomes via Screening of Lipid Switches Designed to Undergo Conformational Changes upon Binding Phosphorylated Metabolites
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DOI：
10.1021/jacs.2c00191
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发表时间：
2022-03-02
影响因子：
15
通讯作者：
Best, Michael D.
中科院分区：
文献类型：
--
作者：
Lou, Jinchao;Schuster, Jennifer A.;Best, Michael D.
脂质体给药载体可以极大地促进药物的传输。然而，它们的临床应用需要加强对病变部位内容释放的控制。出于这个原因，已经探索了触发释放策略，尽管到目前为止已经开发了有限的刺激工具箱。在这里，我们报告了一种新的策略，刺激响应型脂质体在磷酸化小分子存在的情况下释放包裹的内容物。我们的配方努力达到了由ATP驱动的选择性货物释放的顶峰，ATP是一种普遍的能源，在癌症等疾病中上调。具体地说，我们开发了带有两个ZnDPA单元的脂质开关1a-b，设计用于在ATP结合时经历实质性的构象变化，从而扰乱膜包装并触发包膜内容物的释放。利用疏水性染料尼罗红进行的染料渗漏实验证实，ATP驱动的释放对11种类似的磷酸化代谢物具有选择性，同时也实现了亲水性染料钙黄绿素的释放。合成和研究了多种可供选择的脂质开关结构(1c-d和2)，这些结构特征使1a-b对ATP驱动的释放具有选择性。重要的是，结合药物ATP操作结合荧光显微镜对细胞递送的分析表明，脂质体递送是特异的，因为它随着细胞内ATP积累的增加而增加，并受到ATP下调的抑制。我们的新方法显示出强大的前景，可以提高由代谢产物如三磷酸腺苷驱动的对患病细胞的释放和有效载荷传递的选择性，为控制释放提供一个令人兴奋的新范式。
Liposomal delivery vehicles can dramatically enhance drug transport. However, their clinical application requires enhanced control over content release at diseased sites. For this reason, triggered release strategies have been explored, although a limited toolbox of stimuli has thus far been developed. Here, we report a novel strategy for stimuli-responsive liposomes that release encapsulated contents in the presence of phosphorylated small molecules. Our formulation efforts culminated in selective cargo release driven by ATP, a universal energy source that is upregulated in diseases such as cancer. Specifically, we developed lipid switches 1a-b bearing two ZnDPA units designed to undergo substantial conformational changes upon ATP binding, thereby disrupting membrane packing and triggering the release of encapsulated contents. Dye leakage assays using the hydrophobic dye Nile red validated that ATP-driven release was selective over 11 similar phosphorylated metabolites, and release of the hydrophilic dye calcein was also achieved. Multiple alternative lipid switch structures were synthesized and studied (1c-d and 2), which provided insights into the structural features that render 1a-b selective toward ATP-driven release. Importantly, analysis of cellular delivery using fluorescence microscopy in conjunction with pharmacological ATP manipulation showed that liposome delivery was specific, as it increased upon intracellular ATP accumulation, and was inhibited by ATP downregulation. Our new approach shows strong prospects for enhancing the selectivity of release and payload delivery to diseased cells driven by metabolites such as ATP, providing an exciting new paradigm for controlled release.