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.

Molybdenum disulfide/graphene oxide nanocomposites show favorable lung targeting and enhanced drug loading/tumor-killing efficacy with improved biocompatibility

“…In contrast, GO was well dispersed in water and culture medium with the hydrodynamic size from 200 to 270 nm (Supplementary Figure S5), consistent with previous reports. 9,10,46 Owing to the abundant oxygen-containing functional groups on its surface, GO exhibits excellent dispersity in water, which is a crucial prerequisite for its biomedical applications. 21 As a result, MoS 2 /GO manifested great dispersity in water and cell culture medium with 10% FBS, similar to Lys-MoS 2 and FA-MoS 2 , and the hydrodynamic size was considerably reduced to 140-160 nm in water and 180-270 nm in culture medium, respectively (Supplementary Figure S5, Po0.05).…”

“…Of note, unlike other nanomaterials, graphene oxide (GO) is able to localize in the lung through various exposure routes (for example, intravenous (i.v.) administration), [9][10][11][12] being ascribed to the formation of GO-protein complexes that were readily caught by lung capillary vessels. [13][14][15] GO's selective localization in the lung distinguishes it from other types of nanomaterials (mostly in liver and spleen), 16,17 offering a 'guided missile' to target the lung.…”

“…[18][19][20][21] For instance, our recent reports revealed an active interaction between GO and macrophages, inducing macrophagic pro-inflammatory responses, necrosis, cellular injuries and fibrosis. 9,10,22 Therefore, improving GO's biocompatibility becomes a crucial prerequisite prior to expanding its bio-applications.…”

“…28,32 In contrast, GO is highly soluble in aqueous solutions with a pronounced ability to target the lung. 9,10,21 Emerging evidence reports the applications of MoS 2 /GO nanocomposites in bioscience. [33][34][35] For instance, MoS 2 /GO nanocomposites revealed a greater antibacterial activity, 33 and enhanced selectivity and sensitivity in detecting glucose and hydrogen peroxide (H 2 O 2 ).…”

Graphene Oxide/Ag Nanoparticles Cooperated with Simvastatin as a High Sensitive X‐Ray Computed Tomography Imaging Agent for Diagnosis of Renal Dysfunctions

“…Therefore, the diagnosis of GO/AgNPs to renal dysfunction would have important clinical and research significance. Previously, many works [33,34,37,[51][52][53] have been reported that GO can be gradually cleared by both renal excretion, meaning that GO/AgNPs have great potential in diagnosis and treatment of the nephropathy. As can be seen from Figure 6A, after intravenous administration with 0.5-10 mg per kg bw of GO/AgNPs for 36 h, the highquality renal imaging can be clearly observed by enhanced-CT under the protection of 20 mg per kg bw simvastatin.…”