Glutathione-mediated biotransformation in the liver modulates nanoparticle transport
Glutathione-mediated biotransformation in the liver modulates nanoparticle transport
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DOI：
10.1038/s41565-019-0499-6
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发表时间：
2019-09-01
影响因子：
38.3
通讯作者：
Zheng, Jie
中科院分区：
文献类型：
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作者：
Jiang, Xingya;Du, Bujie;Zheng, Jie
肝脏中谷胱甘肽介导的生物转化是一种众所周知的消除小异生物质的解毒过程，但其对纳米颗粒保留，靶向和清除的影响远不如肝脏巨噬细胞摄取了解，即使这两个过程都参与肝脏解毒。通过设计一种可以与血清蛋白结合并被转运到肝脏的巯基可激活的荧光金纳米探针，我们以高特异性对体内生物转化动力学进行了非侵入性成像，并在化学水平上研究了这一过程。我们的研究结果表明，谷胱甘肽从肝细胞流出导致高浓度的谷胱甘肽和半胱氨酸在肝窦，这改变了纳米颗粒表面化学，降低了其对血清蛋白的亲和力，并显着改变其血液潴留，靶向和清除。通过这种生物转化，肝脏解毒，纳米医学翻译中的一个长期障碍，可以变成一座桥梁，以最大限度地提高靶向和最小化纳米毒性。
Glutathione-mediated biotransformation in the liver is a well-known detoxification process to eliminate small xenobiotics, but its impacts on nanoparticle retention, targeting and clearance are much less understood than liver macrophage uptake, even though both processes are involved in liver detoxification. By designing a thiol-activatable fluorescent gold nanoprobe that can bind to serum protein and be transported to the liver, we non-invasively imaged the biotransformation kinetics in vivo at high specificity and examined this process at the chemical level. Our results show that glutathione efflux from hepatocytes results in high local concentrations of both glutathione and cysteine in liver sinusoids, which transforms the nanoparticle surface chemistry, reduces its affinity to serum protein and significantly alters its blood retention, targeting and clearance. With this biotransformation, liver detoxification, a long-standing barrier in nanomedicine translation, can be turned into a bridge toward maximizing targeting and minimizing nanotoxicity.