Intracellular Delivery of Functional Proteins and Native Drugs by Cell-Penetrating Poly(disulfide)s
Intracellular Delivery of Functional Proteins and Native Drugs by Cell-Penetrating Poly(disulfide)s
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DOI：
10.1021/jacs.5b08130
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发表时间：
2015-09-23
影响因子：
15
通讯作者：
Yao, Shao Q.
中科院分区：
文献类型：
--
作者：
Fu, Jiaqi;Yu, Changmin;Yao, Shao Q.
将生物活性化合物有效地递送到细胞中是药物发现中的主要挑战。我们在此报告的新方法的发展，细胞内交付的功能蛋白质（包括抗体）和天然小分子药物，通过利用细胞穿透聚（二硫化物）（CPD）。CPD最近被证明是迅速采取了哺乳动物细胞内吞作用的独立途径，但其应用程序的蛋白质和天然小分子药物的交付尚未得到证明。利用我们新开发的CPD辅助方法，在水性条件下，用预合成的CPD在两个步骤中在几分钟内进行货物的快速和“生物正交”装载。将所得CPD-货物缀合物立即用于随后的细胞递送研究。由于这些方法的多功能性和灵活性，我们进一步表明它们可以用于以最少的化学和遗传操作立即递送各种功能性货物。这些CPD及其负载货物的缀合物的最小细胞毒性进一步突出了这种新的细胞转导方法相对于其他现有策略的独特优势，并确保我们的整个递送方案与随后的活细胞实验和生物学研究兼容。
The efficient delivery of bioactive compounds into cells is a major challenge in drug discovery. We report herein the development of novel methods for intracellular delivery of functional proteins (including antibodies) and native small-molecule drugs by making use of cell-penetrating poly(disulfide)s (CPDs). CPDs were recently shown to be rapidly taken up by mammalian cells in endocytosis-independent pathways, but their applications for delivery of proteins and native small-molecule drugs have not been demonstrated. With our newly developed, CPD-assisted approaches, rapid and "bioorthogonal" loading of cargos was carried out with pre-synthesized CPDs, in two steps and in a matter of minutes under aqueous conditions. The resulting CPD-cargo conjugates were used immediately for subsequent cell delivery studies. With the versatility and flexibility of these methods, we further showed that they could be used for immediate delivery of a variety of functional cargos with minimum chemical and genetic manipulations. The minimal cell cytotoxicity of these CPDs and their cargo-loaded conjugates further highlights the unique advantage of this new cell-transduction method over other existing strategies and ensures that our entire delivery protocol is compatible with subsequent live-cell experiments and biological studies.