Cellular uptake of biotransformed graphene oxide into lung cells

Since its first mechanical exfoliation in 2004, graphene has attracted enormous attention as a material with broad potential applications in developing energy storage devices and sensors, catalysis, separation processes, development of novel composites, and biomedicine [[1], [2], [3], [4], [5], [6], [7]]. Especially in biomedicine, graphene oxide has great potential in developing biosensors, drug carriers, tissue engineering, and novel strategies for bioimaging and cancer treatment [8]. However, the use of graphene in medicine is limited due to its high hydrophobicity.

The oxidized form of graphene called graphene oxide (GO) has hydrophilic, oxygen-containing surface groups such as hydroxyl and carboxyl. As a result, GO is more hydrophilic than graphene and can be covalently functionalized by modifying oxygen groups, which, combined with a high surface area of graphene materials, makes it an excellent candidate for drug carriers [[9], [10], [11]]. Hence, many research groups have developed graphene oxide-based drug carriers with high loading capacity, selective towards targeted cells, or with implemented controlled release systems [12,13]. Unfortunately, despite promising results, none of these carriers were approved by FDA or passed to clinical trials. One of the issues is the knowledge gap about the biological properties of GO regarding its internalization by mammalian cells.

One of the aspects of graphene oxide biological behavior which requires further investigation is its cellular uptake mechanisms. GO internalization into the cells is affected by several factors, such as particle dimensions and surface modifications [14]. Several research groups previously examined the role of these parameters [[15], [16], [17]]. In general, graphene oxide enters the cells via endocytic pathways. Particles with dimensions of several hundreds of nanometers or less are internalized by macropinocytosis, whereas larger particles undergo phagocytosis or do not enter the cells at all [18]. As far as a surface modification is concerned, particles presented on the particle surface may mediate internalization. On the other hand, a change in surface charge caused by modification may lead to electrostatic repulsion between the particle and a cell membrane, which may result in uptake inhibition [[19], [20], [21]].

Although much has been done, there are challenges regarding the GO internalization studies that must be addressed. The physicochemical properties of graphene oxide may differ between the two samples due to the alterations in its synthesis. These factors affect the internalization process, which may subsequently lead to discrepancies in data gathered in two separate research groups. Moreover, it is challenging to synthesize GO particles with uniform dimensions, and size separation methods do not guarantee homogenous samples. As a result, there is still a need for GO uptake studies to enrich gathered data and exclude discrepancies. Another aspect of graphene oxide biological studies that requires further investigation is the impact of its interaction with biological fluids on its final internalization into the cells. When nanomaterial is introduced into the living organism, it has contact with biological fluids such as blood or digestion juice. It is an environment rich in biologically active compounds which may interact with nanoparticles simply adsorbing onto nanomaterial surface or by degradation of bonds within GO structure. This phenomenon involves molecule adsorption onto nanomaterial surfaces and changes in its structure as a form of biotransformation. Interactions between graphene oxide and biological fluid may alter the surface properties of graphene oxide, which may change the way it is internalized into the cells. Since one of the potential applications of graphene oxide is the development of novel drug carriers, it is crucial to elucidate the effect of biotransformation on its interactions with cells. Despite the publication of several papers regarding this matter, very little is known about GO impact on the cellular uptake mechanism.

In this research article, the abovementioned challenges will be addressed. First, graphene oxide was thoroughly characterized regarding its chemical structure, cytotoxicity, and internalization into lung cells. In addition, samples with different average diameter sizes and samples that underwent biotransformation were obtained. Then their cytotoxicity and cellular uptake efficiency were systematically evaluated on lung cancer (A549) and lung fibroblasts (LL24) cell lines. In further perspective, it will enrich the data pool regarding GO biological properties and help fill a knowledge gap in understanding graphene oxide interactions in biological systems.

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