文獻(xiàn)：Endocytic Mechanisms of Graphene Oxide Nanosheets in Osteoblasts, Hepatocytes and Macrophages

作者：Javier Linares?M. Concepción Matesanz?Mercedes Vila?§⊥M. José Feito?Gil Gon?alves⊥María Vallet-Regí?§Paula A. A. P. Marques⊥M. Teresa Portolés

文獻(xiàn)鏈接：https://pubs.acs.org/doi/abs/10.1021/am5031598

摘要：

Nano-graphene oxide (GO) has attracted great interest in nanomedicine due to its own intrinsic properties and its possible biomedical applications such as drug delivery, tissue engineering and hyperthermia cancer therapy. However, the toxicity of GO nanosheets is not yet well-known and it is necessary to understand its entry mechanisms into mammalian cells in order to avoid cell damage and human toxicity. In the present study, the cellular uptake of pegylated GO nanosheets of ca. 100 nm labeled with fluorescein isothiocyanate (FITC-PEG-GOs) has been evaluated in the presence of eight inhibitors (colchicine, wortmannin, amiloride, cytochalasin B, cytochalasin D, genistein, phenylarsine oxide and chlorpromazine) that specifically affect different endocytosis mechanisms. Three cell types were chosen for this study: human Saos-2 osteoblasts, human HepG2 hepatocytes and murine RAW-264.7 macrophages. The results show that different mechanisms take part in FITC-PEG-GOs uptake, depending on the characteristics of each cell type. However, macropinocytosis seems to be a general internalization process in the three cell lines analyzed. Besides macropinocytosis, FITC-PEG-GOs can enter through pathways dependent on microtubules in Saos-2 osteoblasts, and through clathrin-dependent mechanisms in HepG2 hepatocytes and RAW-264.7 macrophages. HepG2 cells can also phagocytize FITC-PEG-GOs. These findings help to understand the interactions at the interface of GO nanosheets and mammalian cells and must be considered in further studies focused on their use for biomedical applications.

納米氧化苯（GO）由于其固有的性質(zhì)及其在藥物輸送、組織工程和熱療等生物醫(yī)學(xué)領(lǐng)域的潛在應(yīng)用，引起了人們對納米醫(yī)學(xué)的極大興趣。然而，GO納米片的毒性尚不清楚，有必要了解其進(jìn)入哺乳動物細(xì)胞的機(jī)制，以避免細(xì)胞損傷和人體毒性。

在本研究中，在八種抑制劑（秋水仙素、渥曼寧、阿米洛利、細(xì)胞松弛素B、細(xì)胞松弛蛋白D、染料木素、苯胂氧化物和氯丙嗪）的存在下，評估了用異硫氰酸熒光素（FITC-PEG-GO）標(biāo)記的約100nm的聚乙二醇化GO納米片的細(xì)胞攝取，這些抑制劑專門影響不同的內(nèi)吞機(jī)制。

本研究選擇了三種細(xì)胞類型：人Saos-2成骨細(xì)胞、人HepG2肝細(xì)胞和小鼠RAW-264.7巨噬細(xì)胞。

結(jié)果表明，根據(jù)每種細(xì)胞類型的特征，不同的機(jī)制參與了FITC-PEG-GOs的攝取。然而，在所分析的三種細(xì)胞系中，大顆粒細(xì)胞增多似乎是一個普遍的內(nèi)化過程。除了巨噬細(xì)胞作用外，F(xiàn)ITC-PEG-GOs還可以通過Saos-2成骨細(xì)胞中依賴微管的途徑進(jìn)入，并通過HepG2肝細(xì)胞和RAW-264.7巨噬細(xì)胞中的網(wǎng)格蛋白依賴機(jī)制進(jìn)入。

HepG2細(xì)胞也可以吞噬FITC-PEG-GOs。這些發(fā)現(xiàn)有助于理解GO納米片和哺乳動物細(xì)胞界面上的相互作用，在進(jìn)一步研究其在生物醫(yī)學(xué)應(yīng)用中的應(yīng)用時必須加以考慮。

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