title: Improved In Vitro and In Vivo Biocompatibility of Graphene Oxide through Surface Modification: Poly(Acrylic Acid)-Functionalization is Superior to PEGylation.
abstract: 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.
authors: State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences , Beijing 100085, China.
authors: Ming
authors: M
authors: Xu
authors: 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.
authors: Jianqiang
authors: J
authors: Zhu
authors: College of Environmental Science and Engineering, Ministry of Education Key Laboratory of Pollution Processes and Environmental Criteria, Tianjin Key Laboratory of Environmental Remediation and Pollution Control, Nankai University , Tianjin 300071, China.
authors: Fanfan
authors: F
authors: Wang
authors: Research Center of Biomedical Engineering, Department of Biomaterials, College of Materials, Xiamen University , Xiamen 361005, China.
authors: Yunjing
authors: Y
authors: Xiong
authors: State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences , Beijing 100085, China.
authors: Yakun
authors: Y
authors: Wu
authors: Research Center of Biomedical Engineering, Department of Biomaterials, College of Materials, Xiamen University , Xiamen 361005, China.
authors: Qiuquan
authors: Q
authors: Wang
authors: Research Center of Biomedical Engineering, Department of Biomaterials, College of Materials, Xiamen University , Xiamen 361005, China.
authors: Jian
authors: J
authors: Weng
authors: Department of Urology, The Second Hospital of Tianjin Medical University, Tianjin Institute of Urology , Tianjin 300211, China.
authors: Zhihong
authors: Z
authors: Zhang
authors: College of Environmental Science and Engineering, Ministry of Education Key Laboratory of Pollution Processes and Environmental Criteria, Tianjin Key Laboratory of Environmental Remediation and Pollution Control, Nankai University , Tianjin 300071, China.
authors: Wei
authors: W
authors: Chen
authors: State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences , Beijing 100085, China.
authors: Sijin
authors: S
authors: Liu
mesh_terms: D000180:Acrylic Resins / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity; D000818:Animals; D001672:Biocompatible Materials / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity; D002460:Cell Line; D004705:Endocytosis; D006108:Graphite / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010087:Oxides / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity; D011092:Polyethylene Glycols / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity; D000066970:Protein Corona / Q000032:analysis / Q000378:metabolism; D013499:Surface Properties
chemical_list: D000180:Acrylic Resins; D001672:Biocompatible Materials; D010087:Oxides; D000066970:Protein Corona; D011092:Polyethylene Glycols; C006903:carbopol 940; D006108:Graphite
keywords: biocompatibility; biological mechanisms; derivatives; graphene oxide; surface modification