Biodistribution and elimination of metallic nanobiomaterials
Biodistribution and elimination of gold nanoparticles in vivo
Many investigations on the toxic effects of GNPs have been performed. Generally, the nanoparticles (NPs) can induce oxidative stress, cell apoptosis, and damage of DNA, mitochondria, and cell membranes, leading to adverse effects on cells (Elsaesser and Howard, 2012). In comparing various types of metal NPs, many reports have shown that GNPs have less toxicity than others. The concentration and the surface of GNPs are likely to be the key factor on toxic induction. The recent review by Alkilany and Murphy (2010) has shown that the surface of GNPs plays a major role on the toxic effect. However, the effect of size, shape, zeta potential value, and even exposure time of GNPs on toxic induction cannot be avoided. Mironava et al. (2010) reported that different sizes of spherical GNPs lead to different penetration pathways and cellular uptakes. This can result in different impacts on biological responses of cells and tissues. The recent review by Shang et al. (2014) has demonstrated that the smaller the size of the NPs, the higher the toxic effects. In the case of zeta potential values, it was reported that the cellular uptakes of different values of zeta potential of GNRs were dissimilar, and the inflammatory cytokine inductions of cells treated with these GNRs were also different (Pissuwan et al., 2013).
Nevertheless, due to the higher complexity and variation of in vivo systems, it is important to evaluate the toxic effect of GNPs in vivo. Likewise, in vitro, the impact of GNPs on in vivo toxicity also depends on size, shape, concentration, exposure time, and surface property of GNPs. The other factor that is very important on toxic induction by GNPs in vivo is the administration route of GNPs. It was reported that the injection of 13.5 nm spherical GNPs in mice through oral and intraperitoneal routes caused a higher toxicity than that of the tail-vein route. However, it seems that size and surface properties of GNPs play a major role in the in vivo biological activities. It is commonly known that GNPs without good surface stabilizers could lead to aggregation in biological fluid (Zhang et al., 2012) and then cause aggregation in organs (Jong et al., 2010). It was reported that the major organs where the accumulation of different surface coatings of GNPs were detected were the liver and spleen (De Jong et al., 2008; Morais et al., 2012).
The injection of cetyltrimethylammonium bromide (CTAB)-GNRs through an intravenous route showed that they were mainly accumulated in the liver and spleen after administration for one day and 6 days. However, GNRs coated with polyethylene glycol (PEG-GNRs) still circulated in the blood and were mostly accumulated in the spleen and then the liver at day 6 after administration. These results showed evidence that the surface coating of GNRs also impacts the distribution of particles in vivo (Lankveld et al., 2011). It was reported that the possibility of different distributions of CTAB-GNRs and PEG-GNRs should be affected from the binding degree of opsonin proteins to GNRs. These proteins can enhance cellular uptake by cells in the reticuloendothelial system, resulting in the rapid clearance of CTAB-GNRs from blood (Zhang et al., 2012). Different shapes of GNPs also affected biodistribution. Wang et al. (2015) demonstrated that the levels of accumulation between star- and rod-shaped GNPs were different. They found that there was a rapid accumulation in the spleen after intravenous injection of star-shaped GNPs coated with chitosan. In the case of rod-shaped GNPs coated with chitosan, there was a slower rate of accumulation detected than that of starshaped GNPs. The higher accumulations of rod-shaped GNPs in the kidney and lung were higher than star-shaped GNPs. Their results confirm that the shape of GNPs also has an impact on biodistribution.
Besides biodistribution, the knowledge of the elimination process of NPs applied in vivo is essential. Renal clearance is one of the pathways to remove NPs from the body. With this pathway, NPs can be eliminated through glomerular filtration, tubular secretion, and finally urinary excretion (Longmire et al., 2008). It was reported that size, surface property, concentration, and stability of injected NPs are important factors of the clearance process of NPs. Choi et al. (2007) reported that NPs at the hydrodynamic size less than 5.5 nm could be eliminated by the renal clearance. Nevertheless, it is important to not ignore the fact that the initial size of NPs, especially naked NPs, injected into the body can interact with proteins in blood. This interaction can lead to a change in the size of NPs, resulting in the change of a clearance mechanism. In this case, sizes larger than 5.5 nm are faced with the difficulty of overcoming the renal clearance barrier and therefore cannot be removed from the body through urine excretion (Fig. 7.5).
Zhang et al. (2012) investigated the interaction of gold nanoclusters (Au25-NCs) with human blood plasma. They prepared two different surface coatings of Au25-NCs called as GSH-Au25-NCs (glutathione coating gold nanoclusters; size ~2.1 nm) and BSA-Au25-NCs (bovine serum albumin coating gold nanoclusters; size ~8.2 nm) and found that BSA-Au25-NCs formed a larger size (40-80 nm) than GSH-Au25-NCs (5-30 nm) after interacting with human blood plasma for 24 h. They also found that the amount of GSH-Au25-NCs eliminated through renal clearance was higher than that of BSA-Au25-NCs. Their results suggest that the size of NPs was a key factor to removing particles via the renal pathway. However, it seems that not only size has a major impact on renal clearance. The charge of NPs also is involved in the elimination process, as proposed by Him et al. (2011). They reported that a higher number of negative GNPs (carboxylate GNPs) was detected in urine after 24 h intravenous injection rather than positive GNPs (Aminated GNPs).
Hepatic clearance is another important pathway to eliminate NPs from the body. This type of clearance is more complicated than that of the renal clearance. Basically, catabolism and biliary excretion are major mechanisms of hepatic clearance. Phagocytic Kupffer cells play a key role in this clearance, and these cells are reticuloendothelial (liver and spleen). These Kupffer cells can eliminate foreign materi- als/particles through phagocytosis. Besides Kupffer cells, hepatocytes are also the cells in the liver that are involved in the elimination of particles by endocytosis and enzymatic digestion. NPs taken up by hepatocytes are processed in biliary excretion and are further excreted into the bile at the end (Longmire et al., 2008). It was reported that different surface coatings of GNPs were entrapped by both hepatocytes and Kupffer cells (Morais et al., 2012). However, it seems that Kuppfer cells (cells located in the liver) play a major role in the elimination of GNPs injected through an intravenous route (Sadauskas et al., 2007, 2009). As far as we are aware, more information of hepatic clearance of GNPs by hepatocytes and Kupffer cells is required
Figure 7.5 Schematic representing the filtration of nanoparticles through the renal clearance barrier.
and should be further investigated, because the knowledge on elimination GNPs through this clearance system is still scarce.