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Current applications of graphene oxide in nanomedicine.

Wu SY, An SS, Hulme J - Int J Nanomedicine (2015)

Bottom Line: Graphene has attracted the attention of the entire scientific community due to its unique mechanical and electrochemical, electronic, biomaterial, and chemical properties.The water-soluble derivative of graphene, graphene oxide, is highly prized and continues to be intensely investigated by scientists around the world.This review seeks to provide an overview of the currents applications of graphene oxide in nanomedicine, focusing on delivery systems, tissue engineering, cancer therapies, imaging, and cytotoxicity, together with a short discussion on the difficulties and the trends for future research regarding this amazing material.

View Article: PubMed Central - PubMed

Affiliation: Department of Bionanotechnology, Gachon Medical Research Institute, Gachon University, Sungnamsi, Republic of Korea.

ABSTRACT
Graphene has attracted the attention of the entire scientific community due to its unique mechanical and electrochemical, electronic, biomaterial, and chemical properties. The water-soluble derivative of graphene, graphene oxide, is highly prized and continues to be intensely investigated by scientists around the world. This review seeks to provide an overview of the currents applications of graphene oxide in nanomedicine, focusing on delivery systems, tissue engineering, cancer therapies, imaging, and cytotoxicity, together with a short discussion on the difficulties and the trends for future research regarding this amazing material.

No MeSH data available.


Related in: MedlinePlus

Schematic diagram showing proposed toxic mechanisms of GO on T lymphocytes based on the current data. From left to right are p-GO, GO-COOH, and GO-PEI, respectively. Dotted line indicates signal pathway, and full line indicates the way of GO-PEI transport. Reproduced with permission from Ding Z, Zhang Z, Ma H, Chen Y. In vitro hemocompatibility and toxic mechanism of graphene oxide on human peripheral blood T lymphocytes and serum albumin. ACS Appl Mater Interfaces. 2014;6(22):19797–19807.169 Copyright ©2015 American Chemical Society.Abbreviations: Bcl-2, B-cell lymphoma-2; PEI, polyethylenimine; p-GO, pristine graphene oxide; ROS, reactive oxygen species.
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f6-ijn-10-009: Schematic diagram showing proposed toxic mechanisms of GO on T lymphocytes based on the current data. From left to right are p-GO, GO-COOH, and GO-PEI, respectively. Dotted line indicates signal pathway, and full line indicates the way of GO-PEI transport. Reproduced with permission from Ding Z, Zhang Z, Ma H, Chen Y. In vitro hemocompatibility and toxic mechanism of graphene oxide on human peripheral blood T lymphocytes and serum albumin. ACS Appl Mater Interfaces. 2014;6(22):19797–19807.169 Copyright ©2015 American Chemical Society.Abbreviations: Bcl-2, B-cell lymphoma-2; PEI, polyethylenimine; p-GO, pristine graphene oxide; ROS, reactive oxygen species.

Mentions: The in vitro hemocompatibility and genotoxicity of GO with human primary blood components remains a hotly contested issue. Initial studies examining the hemocompatibility of graphene and GO showed that graphene exerted a slightly higher cytotoxic effect than GO due to its strong hydrophobic interaction with cell membranes with both materials exerting insignificant hemolytic effect (up to 75 µg/mL).167 In contrast, Liao et al168 demonstrated that submicron-sized GO sheets induced the greatest hemolytic activity, whereas aggregated graphene sheets exhibited the lowest hemolytic activity. Coating the oxidized sheets with chitosan almost eliminated hemolytic activity. It was concluded that the toxicity of graphene and GO was dependent on the exposure environment (ie, whether or not aggregation occurs) and mode of interaction with cells (ie, suspension versus adherent cell types). In a recent investigation, Ding et al169 examined the hemocompatibility of GO on human peripheral blood T lymphocytes and human serum albumin (HSA). In that work, the underlying toxic mechanisms of pristine GO (p-GO) and functionalized GO (GO-COOH and GO-PEI) to primary human peripheral blood T-lymphocytes and HSA were investigated. p-GO was found to interact directly with the protein receptors to inhibit their ligand-binding ability, leading to ROS-dependent apoptosis through the B-cell lymphoma-2 (Bcl-2) pathway; GO-COOH exhibited a similar degree of toxicity on T lymphocytes except keeping a normal ROS level. Ding et al proposed that GO-COOH inhibits protein-ligand binding and passes the passive apoptosis signal to nucleus DNA through a ROS-independent mechanism. GO-PEI showed severe hematotoxcity to T lymphocytes by inducing membrane damage. For HSA, the binding of GO-COOH resulted in minimal conformational change and HSA’s binding capacity to bilirubin remained unaffected, while the binding of p-GO and GO-PEI exhibited strong toxicity on HSA. A schematic of the toxic mechanism of GO on T lymphocytes is depicted in Figure 6. These apparent contradictions in the literature are most probably due to poor-quality GO being used (broad lateral distributions >500 nm and the presence of contaminants, Mn2+, Fe3+, Cu2+) and inconsistencies in assay design (MTT false positives and GO’s strong autofluorescence signal). At concentrations approximate to 50 µg/mL or higher, freshly prepared GO begins to show toxicity against erythrocytes, fibroblasts, and, in some reports, PC12 cells as well. PEGylation significantly improves biocompatibility, but the chemical bonds linking GO with the surfactant can be broken releasing PEG and its derivatives into the surrounding environment. The influence of PEG to suppress heme destruction and improve peroxidase function was recently reported by Mao et al.170 It was found that horseradish peroxidase (HRP) inactivation is significantly mitigated in the presence of PEG. In addition, recent reports show that the concentration of HRP oligomers produced from the biocatalysis of GO was undetectable.171 It is well reported that carbon nanotubes are rapidly degraded by HRP, myeloperoxidase, eosinophil peroxidase with HRP-catalyzed oxidation of single walled carbon nanotubes and GO (single-walled carbon nanotubes) reported to induce DNA damage.172 Whether the localized release of PEG from modified GO impacts other HRP inactivation pathways and hemotoxicity remains unknown. However, small lateral (l)-sized GO (200 nm) fragments are known to interact with DNA.173 These interactions include DNA intercalation and the scission of DNA by GO/Cu2+ complexes. Furthermore, it has been shown that GO/Mn2+ and GO/Fe2+ complexes also cleave DNA. In addition, several investigations have shown that treatments of various cell lines with carbon nanomaterials such as rGO, graphene, and graphite can elevate the expression of p53, Rad 51, and MOGG1-1 reflecting chromosomal damage. Until recently, it was unclear whether DNA damage induced by graphene-based materials caused mutagenesis. In a recent study by Liu et al174 GO treatments at concentrations of 10 and 100 µg/mL were found to alter gene expression in 101 genes involved in DNA-damage control, cell apoptosis, cell cycle, and metabolism. Intravenous injection of conventionally prepared GO at 4 mg/kg for 5 consecutive days induced formation of micronucleated polychromic erythrocytes in mice, and its mutagenesis potential appeared to be comparable with cyclophosphamide, a classic mutagen. However, traditionally prepared GO often contains high concentrations of Mn2+ (97 ppm) and Fe2+ WC. As stated previously, both metals are highly mutagenic in the presence of GO, nonspecific release of these ions from traditionally prepared GO might result in unusually high levels of toxicity and random scission of DNA. Consequently, researchers have started to use nontoxic oxidizing agents with greener exfoliating methods.175 Of particular note is the recent work by Peng et al176 in which an Fe2+-based green strategy produced a single layer of GO in just 1 hour. Their approach resulted in the production of high purity GO containing 0.025 ppm of Mn2+ and 0.13 ppm Fe2+, respectively. Results regarding the cytotoxicity of graphene-based nanomaterials remain conflicting (particular for GO). These discrepancies may be due to differences in the quality of the nanomaterials tested.177,178


Current applications of graphene oxide in nanomedicine.

Wu SY, An SS, Hulme J - Int J Nanomedicine (2015)

Schematic diagram showing proposed toxic mechanisms of GO on T lymphocytes based on the current data. From left to right are p-GO, GO-COOH, and GO-PEI, respectively. Dotted line indicates signal pathway, and full line indicates the way of GO-PEI transport. Reproduced with permission from Ding Z, Zhang Z, Ma H, Chen Y. In vitro hemocompatibility and toxic mechanism of graphene oxide on human peripheral blood T lymphocytes and serum albumin. ACS Appl Mater Interfaces. 2014;6(22):19797–19807.169 Copyright ©2015 American Chemical Society.Abbreviations: Bcl-2, B-cell lymphoma-2; PEI, polyethylenimine; p-GO, pristine graphene oxide; ROS, reactive oxygen species.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4554423&req=5

f6-ijn-10-009: Schematic diagram showing proposed toxic mechanisms of GO on T lymphocytes based on the current data. From left to right are p-GO, GO-COOH, and GO-PEI, respectively. Dotted line indicates signal pathway, and full line indicates the way of GO-PEI transport. Reproduced with permission from Ding Z, Zhang Z, Ma H, Chen Y. In vitro hemocompatibility and toxic mechanism of graphene oxide on human peripheral blood T lymphocytes and serum albumin. ACS Appl Mater Interfaces. 2014;6(22):19797–19807.169 Copyright ©2015 American Chemical Society.Abbreviations: Bcl-2, B-cell lymphoma-2; PEI, polyethylenimine; p-GO, pristine graphene oxide; ROS, reactive oxygen species.
Mentions: The in vitro hemocompatibility and genotoxicity of GO with human primary blood components remains a hotly contested issue. Initial studies examining the hemocompatibility of graphene and GO showed that graphene exerted a slightly higher cytotoxic effect than GO due to its strong hydrophobic interaction with cell membranes with both materials exerting insignificant hemolytic effect (up to 75 µg/mL).167 In contrast, Liao et al168 demonstrated that submicron-sized GO sheets induced the greatest hemolytic activity, whereas aggregated graphene sheets exhibited the lowest hemolytic activity. Coating the oxidized sheets with chitosan almost eliminated hemolytic activity. It was concluded that the toxicity of graphene and GO was dependent on the exposure environment (ie, whether or not aggregation occurs) and mode of interaction with cells (ie, suspension versus adherent cell types). In a recent investigation, Ding et al169 examined the hemocompatibility of GO on human peripheral blood T lymphocytes and human serum albumin (HSA). In that work, the underlying toxic mechanisms of pristine GO (p-GO) and functionalized GO (GO-COOH and GO-PEI) to primary human peripheral blood T-lymphocytes and HSA were investigated. p-GO was found to interact directly with the protein receptors to inhibit their ligand-binding ability, leading to ROS-dependent apoptosis through the B-cell lymphoma-2 (Bcl-2) pathway; GO-COOH exhibited a similar degree of toxicity on T lymphocytes except keeping a normal ROS level. Ding et al proposed that GO-COOH inhibits protein-ligand binding and passes the passive apoptosis signal to nucleus DNA through a ROS-independent mechanism. GO-PEI showed severe hematotoxcity to T lymphocytes by inducing membrane damage. For HSA, the binding of GO-COOH resulted in minimal conformational change and HSA’s binding capacity to bilirubin remained unaffected, while the binding of p-GO and GO-PEI exhibited strong toxicity on HSA. A schematic of the toxic mechanism of GO on T lymphocytes is depicted in Figure 6. These apparent contradictions in the literature are most probably due to poor-quality GO being used (broad lateral distributions >500 nm and the presence of contaminants, Mn2+, Fe3+, Cu2+) and inconsistencies in assay design (MTT false positives and GO’s strong autofluorescence signal). At concentrations approximate to 50 µg/mL or higher, freshly prepared GO begins to show toxicity against erythrocytes, fibroblasts, and, in some reports, PC12 cells as well. PEGylation significantly improves biocompatibility, but the chemical bonds linking GO with the surfactant can be broken releasing PEG and its derivatives into the surrounding environment. The influence of PEG to suppress heme destruction and improve peroxidase function was recently reported by Mao et al.170 It was found that horseradish peroxidase (HRP) inactivation is significantly mitigated in the presence of PEG. In addition, recent reports show that the concentration of HRP oligomers produced from the biocatalysis of GO was undetectable.171 It is well reported that carbon nanotubes are rapidly degraded by HRP, myeloperoxidase, eosinophil peroxidase with HRP-catalyzed oxidation of single walled carbon nanotubes and GO (single-walled carbon nanotubes) reported to induce DNA damage.172 Whether the localized release of PEG from modified GO impacts other HRP inactivation pathways and hemotoxicity remains unknown. However, small lateral (l)-sized GO (200 nm) fragments are known to interact with DNA.173 These interactions include DNA intercalation and the scission of DNA by GO/Cu2+ complexes. Furthermore, it has been shown that GO/Mn2+ and GO/Fe2+ complexes also cleave DNA. In addition, several investigations have shown that treatments of various cell lines with carbon nanomaterials such as rGO, graphene, and graphite can elevate the expression of p53, Rad 51, and MOGG1-1 reflecting chromosomal damage. Until recently, it was unclear whether DNA damage induced by graphene-based materials caused mutagenesis. In a recent study by Liu et al174 GO treatments at concentrations of 10 and 100 µg/mL were found to alter gene expression in 101 genes involved in DNA-damage control, cell apoptosis, cell cycle, and metabolism. Intravenous injection of conventionally prepared GO at 4 mg/kg for 5 consecutive days induced formation of micronucleated polychromic erythrocytes in mice, and its mutagenesis potential appeared to be comparable with cyclophosphamide, a classic mutagen. However, traditionally prepared GO often contains high concentrations of Mn2+ (97 ppm) and Fe2+ WC. As stated previously, both metals are highly mutagenic in the presence of GO, nonspecific release of these ions from traditionally prepared GO might result in unusually high levels of toxicity and random scission of DNA. Consequently, researchers have started to use nontoxic oxidizing agents with greener exfoliating methods.175 Of particular note is the recent work by Peng et al176 in which an Fe2+-based green strategy produced a single layer of GO in just 1 hour. Their approach resulted in the production of high purity GO containing 0.025 ppm of Mn2+ and 0.13 ppm Fe2+, respectively. Results regarding the cytotoxicity of graphene-based nanomaterials remain conflicting (particular for GO). These discrepancies may be due to differences in the quality of the nanomaterials tested.177,178

Bottom Line: Graphene has attracted the attention of the entire scientific community due to its unique mechanical and electrochemical, electronic, biomaterial, and chemical properties.The water-soluble derivative of graphene, graphene oxide, is highly prized and continues to be intensely investigated by scientists around the world.This review seeks to provide an overview of the currents applications of graphene oxide in nanomedicine, focusing on delivery systems, tissue engineering, cancer therapies, imaging, and cytotoxicity, together with a short discussion on the difficulties and the trends for future research regarding this amazing material.

View Article: PubMed Central - PubMed

Affiliation: Department of Bionanotechnology, Gachon Medical Research Institute, Gachon University, Sungnamsi, Republic of Korea.

ABSTRACT
Graphene has attracted the attention of the entire scientific community due to its unique mechanical and electrochemical, electronic, biomaterial, and chemical properties. The water-soluble derivative of graphene, graphene oxide, is highly prized and continues to be intensely investigated by scientists around the world. This review seeks to provide an overview of the currents applications of graphene oxide in nanomedicine, focusing on delivery systems, tissue engineering, cancer therapies, imaging, and cytotoxicity, together with a short discussion on the difficulties and the trends for future research regarding this amazing material.

No MeSH data available.


Related in: MedlinePlus