Review of health safety aspects of nanotechnologies in food production.

Due to new, previously unknown, properties attributed to engineered nanoparticles many new products are introduced in the agro-food area. Nanotechnologies cover many aspects, such as disease treatment, food security, new materials for pathogen detection, packaging materials and delivery systems. As with most new and evolving technologies, potential benefits are emphasized, while little is known on safety of the application of nanotechnologies in the agro-food sector. This review gives an overview of scientific issues that need to be addressed with priority in order to improve the risk assessment for nanoparticles in food. The following research topics are considered to contribute pivotally to risk assessment of nanotechnologies and nanoparticles in food products. Set a definition for NPs to facilitate regulatory discussions, prioritization of research and exchange of study results. Develop analytical tools for the characterization of nanoparticles in complex biological matrices like food. Establish relevant dose metrics for nanoparticles used for both interpretation of scientific studies as well as regulatory frameworks. Search for deviant behavior (kinetics) and novel effects (toxicity) of nanoparticles and assess the validity of currently used test systems following oral exposure. Estimate the consumer exposure to nanoparticles.

Particle size-dependent organ distribution of gold nanoparticles after intravenous administration.

A kinetic study was performed to determine the influence of particle size on the in vivo tissue distribution of spherical-shaped gold nanoparticles in the rat. Gold nanoparticles were chosen as model substances as they are used in several medical applications. In addition, the detection of the presence of gold is feasible with no background levels in the body in the normal situation. Rats were intravenously injected in the tail vein with gold nanoparticles with a diameter of 10, 50, 100 and 250 nm, respectively. After 24 h, the rats were sacrificed and blood and various organs were collected for gold determination. The presence of gold was measured quantitatively with inductively coupled plasma mass spectrometry (ICP-MS). For all gold nanoparticle sizes the majority of the gold was demonstrated to be present in liver and spleen. A clear difference was observed between the distribution of the 10 nm particles and the larger particles. The 10 nm particles were present in various organ systems including blood, liver, spleen, kidney, testis, thymus, heart, lung and brain, whereas the larger particles were only detected in blood, liver and spleen. The results demonstrate that tissue distribution of gold nanoparticles is size-dependent with the smallest 10nm nanoparticles showing the most widespread organ distribution.

What do we (need to) know about the kinetic properties of nanoparticles in the body?

Nowadays the development and applications of nanotechnology are of major importance in both industrial and consumer areas. However, the knowledge on human exposure and possible toxicity of nanotechnology products is limited. To understand the mechanism of toxicity, thorough knowledge of the toxicokinetic properties of nanoparticles is warranted. There is a need for information on the absorption, distribution, metabolism and excretion (ADME) of nanoparticles and validated detection methods of these man-made nanoparticles. Determination of the ADME properties of nanoparticles requires specialised detection methods in different biological matrices (e.g. blood and organs). In this paper, the current knowledge on the kinetic properties of nanoparticles is reviewed. Moreover, knowledge gaps from a kinetic point of view (detection, dose, ADME processes) are identified.

Targeting 15d-prostaglandin J2 to hepatic stellate cells: two options evaluated.

PURPOSE: Delivery of apoptosis-inducing compounds to hepatic stellate cells (HSC) may be an effective strategy to reverse liver fibrosis. The aim of this study was therefore to examine the selective targeting of the apoptosis-inducing drug 15-deoxy-delta12,14-prostaglandin J2 (15dPGJ2) with two different HSC-carriers: human serum albumin modified with the sugar mannose-6-phosphate (M6PHSA) or albumin modified with PDGF-receptor recognizing peptides (pPBHSA). METHODS AND RESULTS: After chemical conjugation of 15dPGJ2 to the carriers, the constructs displayed pharmacological activity and specific receptor-mediated binding to HSC in vitro. Unlike 15dPGJ2-pPBHSA, the cellular binding of 15dPGJ2-M6PHSA was reduced by a scavenger receptor antagonist. In vivo, both conjugates rapidly accumulated in fibrotic livers. Intrahepatic analysis revealed that 15dPGJ2-M6PHSA mainly accumulated in HSC, and to a lesser extent in Kupffer cells. 15dPGJ2-pPBHSA also predominantly accumulated in HSC with additional uptake in hepatocytes. Assessment of target receptors in human cirrhotic livers revealed that M6P/IGFII-receptor expression was present in fibrotic areas. PDGF-P receptor expression was abundantly expressed on human fibroblasts. CONCLUSIONS: These studies show that 15dPGJ2 coupled to either M6PHSA or pPBHSA is specifically taken up by HSC and is highly effective within these cells. Both carriers differ with respect to receptor specificity, leading to differences in intrahepatic distribution. Nevertheless, both carriers can be used to deliver the apoptosis-inducing drug 15dPGJ2 to HSC in vivo.

Gliotoxin non-selectively induces apoptosis in fibrotic and normal livers.

BACKGROUND: Liver fibrosis is the common response to chronic liver injury, ultimately leading to cirrhosis. Several lines of evidence indicate that inducing apoptosis of hepatic stellate cells (HSC) may lead to regression of liver fibrosis. Recently, it was shown that gliotoxin (GTX) induces apoptosis of HSC. However, the clinical use of GTX may be limited because of the lack of cell and tissue specificity, causing a high risk of potentially severe adverse effects. The aim of this study, therefore, was to study the effect of GTX on different cells of the liver. METHODS: We used normal and fibrotic precision-cut rat liver slices to study the effect of GTX on the various resident liver cell types. In these slices, the complex cell-cell interactions are preserved, which closely mimics the in vivo situation. RESULTS: GTX exhibited a potent apoptosis-inducing activity in these slices. Both immunohistochemical stainings and real-time mRNA techniques showed that this apoptosis-inducing effect was seen in HSC. However, Kupffer cells and liver endothelial cells were also affected by GTX, whereas hepatocytes were only mildly affected. CONCLUSIONS: This study indicates that the apoptosis-inducing strategy to treat liver fibrosis has high potential, but it will be necessary to develop an HSC-specific therapy to prevent adverse effects.

Pharmacokinetic and biodistribution profile of recombinant human interleukin-10 following intravenous administration in rats with extensive liver fibrosis.

PURPOSE: Because interleukin-10 (IL-10) seems a promising new antifibrotic drug, we investigated the pharmacokinetic and biodistribution profile of this potent therapeutic cytokine in rats with extensive liver fibrosis (BDL-3). IL-10 receptor expression was also determined in relation to these aspects. METHODS: To study the pharmacokinetic and biodistribution of IL-10, rhIL-10 was labeled with 125-iodine. Plasma samples of 125IrhIL-10 were obtained over a 30-min time period after administration of radiolabeled-cytokine to BDL-3 and normal rats. The tissue distribution was assessed 10 and 30 min after i.v. administration of 125IrhlL-10. IL-10 receptor expression was determined by immurohistochemical staining and RT-PCR technique. RESULTS: . The 125IrhIL-10 plasma curves followed two-compartment kinetics with a lower AUC in BDL-3 rats as compared to control. Plasma clearance and distribution volume at steady state were larger in BDL-3 rats. Tissue distribution analysis in normal rats showed that 125IrhIL-10 highly accumulated in kidneys. In BDL-3 rats, the liver content of 125IrhIL-10 increased by a factor of 2, whereas kidney accumulation did not significantly change. Immunohistochemical staining and RT-PCR analysis showed that IL-10 receptor was clearly upregulated in BDL-3 rat livers. CONCLUSIONS: . In normal rats, 125IrhIL-10 rapidly disappears from the circulation, and the kidney is predominantly responsible for this. In BDL-3 rats, the liver largely contributes to this rapid plasma disappearance, probably due to an increase in IL-10 receptor expression. The extensive renal clearance of IL-10 in vivo may limit a clinical application of this cytokine for the treatment of chronic liver diseases. To optimize the therapeutic effects of IL-10 in hepatic diseases, alternative approaches that either decrease renal disposition or that further enhance hepatic delivery should be considered.