State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences , Beijing 100085, China.
Department of Urology, The Second Hospital of Tianjin Medical University, Tianjin Institute of Urology , Tianjin 300211, China.
ACS Nano. 2016 Mar 22;10(3):3267-81. doi: 10.1021/acsnano.6b00539. Epub 2016 Feb 15.
The unique physicochemical properties of two-dimensional (2D) graphene oxide (GO) could greatly benefit the biomedical field; however, recent research demonstrated that GO could induce in vitro and in vivo toxicity. We determined the mechanism of GO induced toxicity, and our in vitro experiments revealed that pristine GO could impair cell membrane integrity and functions including regulation of membrane- and cytoskeleton-associated genes, membrane permeability, fluidity and ion channels. Furthermore, GO induced platelet depletion, pro-inflammatory response and pathological changes of lung and liver in mice. To improve the biocompatibility of pristine GO, we prepared a series of GO derivatives including aminated GO (GO-NH2), poly(acrylamide)-functionalized GO (GO-PAM), poly(acrylic acid)-functionalized GO (GO-PAA) and poly(ethylene glycol)-functionalized GO (GO-PEG), and compared their toxicity with pristine GO in vitro and in vivo. Among these GO derivatives, GO-PEG and GO-PAA induced less toxicity than pristine GO, and GO-PAA was the most biocompatible one in vitro and in vivo. The differences in biocompatibility were due to the differential compositions of protein corona, especially immunoglobulin G (IgG), formed on their surfaces that determine their cell membrane interaction and cellular uptake, the extent of platelet depletion in blood, thrombus formation under short-term exposure and the pro-inflammatory effects under long-term exposure. Overall, our combined data delineated the key molecular mechanisms underlying the in vivo and in vitro biological behaviors and toxicity of pristine GO, and identified a safer GO derivative that could be used for future applications.
二维（2D）氧化石墨烯（GO）具有独特的物理化学性质，这使其在生物医学领域大有用武之地；然而，最近的研究表明，GO 可能会引起体外和体内毒性。我们确定了 GO 诱导毒性的机制，我们的体外实验表明，原始 GO 可能会损害细胞膜的完整性和功能，包括调节与膜和细胞骨架相关的基因、膜通透性、流动性和离子通道。此外，GO 还会诱导血小板耗竭、促炎反应以及小鼠肺和肝的病理变化。为了提高原始 GO 的生物相容性，我们制备了一系列 GO 衍生物，包括氨基化 GO（GO-NH2）、聚丙烯酰胺功能化 GO（GO-PAM）、聚丙烯酸功能化 GO（GO-PAA）和聚乙二醇功能化 GO（GO-PEG），并比较了它们在体外和体内的毒性。在这些 GO 衍生物中，GO-PEG 和 GO-PAA 引起的毒性比原始 GO 低，而 GO-PAA 在体外和体内的生物相容性最好。生物相容性的差异是由于其表面形成的蛋白质冠（特别是免疫球蛋白 G（IgG））的组成不同，这决定了它们与细胞膜的相互作用和细胞摄取、在血液中血小板耗竭的程度、短期暴露下血栓形成以及长期暴露下的促炎作用。总的来说，我们综合的数据描绘了原始 GO 在体内和体外生物行为和毒性的关键分子机制，并确定了一种更安全的 GO 衍生物，可用于未来的应用。
