The biotransformation of graphene oxide in lung fluids significantly alters its inherent properties and bioactivities toward immune cells Yu Qi, Yun Liu, Tian Xia, An Xu, Sijin Liu & Wei Chen NPG Asia Materials volume 10, pages385–396(2018) Cite this article
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Abstract
Engineered nanomaterials (such as graphene oxide, GO) have shown great potential in biomedical applications as therapeutic and imaging agents. However, little is known about their potential transformations in biological settings, which may alter their physicochemical properties and consequently hinder their biomedical applications. Here, we show that GO undergoes a significant physicochemical transformation in two simulated human lung fluids–Gamble’s solution and artificial lysosomal fluid (ALF), as the organic acids (e.g., citrate and acetate) in the lung fluids cause the reduction of GO, which is mainly due to the conversion of epoxy and carbonyl groups to phenolic groups. This biotransformation markedly inhibits the endocytosis of GO by scavenging macrophages. Notably, the alterations that occur in Gamble’s solution enhance the layer-by-layer aggregation of GO, resulting in the precipitation of GO and a reduction in its interaction with cells, whereas the changes that occur in ALF lead to edge-to-edge aggregation of GO, thereby enhancing the adhesion of large sheet-like GO aggregates on the plasma membrane without cellular uptake. The varied interaction mechanisms with macrophages eventually induce different proinflammatory reactions. Experiments conducted in mice corroborated the morphological alterations of GO in a realistic lung microenvironment. Overall, the findings suggest that the biotransformation of nanomaterials may significantly alter their inherent properties and therefore affect their biosafety, such as the clearance of “worn-out” nanomaterials by immune cells, giving rise to potentially long-term side effects at the accumulation sites.
Introduction
Recent advances in nanotechnology provide unprecedented opportunities to facilitate precision medicine initiatives for both therapeutics and diagnostics 1, 2. Thus, a variety of engineered nanomaterials (e.g., graphene oxide, GO) are intensively researched for various therapeutic and imaging purposes 3, 4, 5, 6, 7, 8. Nonetheless, it is necessary to note that all the current biomedical applications are based on the predesigned physicochemical properties of nanomaterials without considering their potential transformation in biological settings, which may alter their physicochemical properties and consequently hinder their biomedical applications. For instance, biotransformations may influence how nanomaterials interact with the immune cells (e.g., macrophages) responsible for clearing the “worn-out” particles out of the body 9, 10. Thus, understanding the potential transformations and their effects on the ultimate fate of nanomaterials is critical for ensuring the biosafety of nanomaterials.
Most nanomaterials predominantly deposit in the lungs after administration either through direct inhalation of a spray or intravenous injection, which depends on the imaging and therapeutic purposes 11, 12. Of note, lung fluids contain an abundance of reactive organic acids and phosphorus, which may induce the oxidation/reduction of nanomaterials. The potential for reaction with these constituents in biological media is particularly relevant for graphene materials (especially GO), as these materials are reactive and prone to reduction, even under relatively mild conditions 13. To date, little is known about the potential transformation of graphene materials in the lungs and the potential implications for biomedical applications.
The primary objective of this study was to prove that nanomaterials undergo significant biotransformations in lung fluids, which may subsequently compromise their biosafety by impeding their clearance by immune cells. GO was selected as the model nanomaterial due to its versatility in biological applications. Here, we show that the alteration of the GO physicochemical properties in two simulated lung fluids—Gamble’s solution and artificial lysosomal fluid (ALF)—greatly hinders its elimination by macrophages via distinctly different mechanisms depending on the specific biological settings involved, which could lead to potentially long-term side effects. Treatment with Gamble’s solution simulates the interaction between GO with the interstitial fluid deep within the lung under healthy conditions. The ALF treatment simulates the scenario in which GO sheets are phagocytosed by macrophages, subsequently rereleased into the lung system once the cells are dead, and then participate in subsequent interaction with other macrophages. Two extracellular and intercellular transformation pathways occur simultaneously in the lung. Overall, our findings may have significant implications for the application of nanomaterials in biomedicine, and they highlight the importance of understanding the in vivo biotransformation of nanomaterials. |
