Hepatic toxicity assessment of cationic liposome exposure in healthy and chronic alcohol fed mice

The utilisation of nanoparticles as the means of targeted delivery of therapeutics and/or imaging agents could greatly enhance the specific transport of biologically active payloads to target tissues while avoiding or reducing undesired side-effects. To allow for this to become a reality, the question of potential toxicological effects needs to be addressed. In the present investigation, a cationic liposome with prospective for medical applications was constructed and thoroughly assessed for any material-induced hepatic adverse effects in vivo − in healthy and alcoholic hepatic disease models and in vitro − (HepG2 cells). The data demonstrated that intravenous injection of liposomes did not cause any significant in vivo hepatic toxicity (inflammation, alterations in blood parameters, anti-oxidant depletion, acute phase response and histopathology) at doses of 200 μg per mouse in either healthy or chronically alcohol fed mice. Additionally, the in vitro material-induced adverse effects (cytotoxicity, inflammation or albumin secretion) were all also minimal. The data from this study demonstrated that the intravenous injection of cationic liposomes does not cause hepatic toxicity. This investigation is important as it investigates the toxicity of a nano-sized material in a model of alcoholic hepatic disease in vitro and in vivo. This is an area of research in the field of nanotoxicology that is currently almost entirely overlooked. Keywords: Toxicology, Nanoparticles, Pharmaceutical scienc

Lung inflammation and genotoxicity following pulmonary exposure to nanoparticles in ApoE-/- mice

<p>Abstract</p> <p>Background</p> <p>The toxic and inflammatory potential of 5 different types of nanoparticles were studied in a sensitive model for pulmonary effects in apolipoprotein E knockout mice (ApoE^-/-). We studied the effects instillation or inhalation Printex 90 of carbon black (CB) and compared CB instillation in ApoE-/- and C57 mice. Three and 24 h after pulmonary exposure, inflammation was assessed by mRNA levels of cytokines in lung tissue, cell composition, genotoxicity, protein and lactate dehydrogenase activity in broncho-alveolar lavage (BAL) fluid.</p> <p>Results</p> <p>Firstly, we found that intratracheal instillation of CB caused far more pulmonary toxicity in ApoE^-/-mice than in C57 mice. Secondly, we showed that instillation of CB was more toxic than inhalation of a presumed similar dose with respect to inflammation in the lungs of ApoE^-/-mice. Thirdly, we compared effects of instillation in ApoE^-/-mice of three carbonaceous particles; CB, fullerenes C₆₀(C₆₀) and single walled carbon nanotubes (SWCNT) as well as gold particles and quantum dots (QDs). Characterization of the instillation media revealed that all particles were delivered as agglomerates and aggregates. Significant increases in <it>Il-6, Mip-2 </it>and <it>Mcp-1 </it>mRNA were detected in lung tissue, 3 h and 24 h following instillation of SWCNT, CB and QDs. DNA damage in BAL cells, the fraction of neutrophils in BAL cells and protein in BAL fluid increased statistically significantly. Gold and C₆₀particles caused much weaker inflammatory responses.</p> <p>Conclusion</p> <p>Our data suggest that ApoE^-/-model is sensitive for evaluating particle induced inflammation. Overall QDs had greatest effects followed by CB and SWCNT with C₆₀and gold being least inflammatory and DNA-damaging. However the gold was used at a much lower mass dose than the other particles. The strong effects of QDs were likely due to Cd release. The surface area of the instilled dose correlated well the inflammatory response for low toxicity particles.</p

Pulmonary exposure to carbon black nanoparticles and vascular effects

<p>Abstract</p> <p>Background</p> <p>Exposure to small size particulates is regarded as a risk factor for cardiovascular diseases.</p> <p>Methods</p> <p>We exposed young and aged apolipoprotein E knockout mice (<it>apoE^-/-</it>) to carbon black (Printex 90, 14 nm) by intratracheal instillation, with different dosing and timing, and measured vasomotor function, progression of atherosclerotic plaques, and VCAM-1, ICAM-1, and 3-nitrotyrosine in blood vessels. The mRNA expression of <it>VCAM-1</it>, <it>ICAM-1</it>, <it>HO-1</it>, and <it>MCP-1 </it>was examined in lung tissue.</p> <p>Results</p> <p>Young <it>apoE^-/-</it>mice exposed to two consecutive 0.5 mg/kg doses of carbon black exhibited lower acetylcholine-induced vasorelaxation in aorta segments mounted in myographs, whereas single doses of 0.05-2.7 mg/kg produced no such effects. The phenylephrine-dependent vasocontraction response was shifted toward a lower responsiveness in the mice exposed once to a low dose for 24 hours. No effects were seen on the progression of atherosclerotic plaques in the aged <it>apoE^-/-</it>mice or on the expression of VCAM-1 and ICAM-1 and the presence of 3-nitrotyrosine in the vascular tissue of either young or aged <it>apoE^-/-</it>mice. The expression of <it>MCP-1 </it>mRNA was increased in the lungs of young <it>apoE^-/-</it>mice exposed to 0.9-2.7 mg/kg carbon black for 24 hours and of aged <it>apoE^-/-</it>mice exposed to two consecutive 0.5 mg/kg doses of carbon black seven and five weeks prior to sacrifice.</p> <p>Conclusion</p> <p>Exposure to nano-sized carbon black particles is associated with modest vasomotor impairment, which is associated neither with nitrosative stress nor with any obvious increases in the expression of cell adhesion proteins on endothelial cells or in plaque progression. Evidence of pulmonary inflammation was observed, but only in animals exposed to higher doses.</p

Modest vasomotor dysfunction induced by low doses of C60 fullerenes in apolipoprotein E knockout mice with different degree of atherosclerosis

<p>Abstract</p> <p>Background</p> <p>Exposure to small size particulate matter in urban air is regarded as a risk factor for cardiovascular effects, whereas there is little information about the impact on the cardiovascular system by exposure to pure carbonaceous materials in the nano-size range. C₆₀fullerenes are nano-sized particles that are expected to have a widespread use, including cosmetics and medicines.</p> <p>Methods</p> <p>We investigated the association between intraperitoneal injection of pristine C₆₀fullerenes and vasomotor dysfunction in the aorta of 11–13 and 40–42 weeks old apolipoprotein E knockout mice (apoE^-/-) with different degree of atherosclerosis.</p> <p>Results</p> <p>The aged apoE^-/-mice had lower endothelium-dependent vasorelaxation elicited by acetylcholine in aorta segments mounted in myographs and the phenylephrine-dependent vasoconstriction response was increased. One hour after an intraperitoneal injection of 0.05 or 0.5 mg/kg of C₆₀fullerenes, the young apoE^-/-mice had slightly reduced maximal endothelium-dependent vasorelaxation. A similar tendency was observed in the old apoE^-/-mice. Hampered endothelium-independent vasorelaxation was also observed as slightly increased EC₅₀of sodium nitroprusside-induced vasorelaxation response in young apoE^-/-mice.</p> <p>Conclusion</p> <p>Treatment with C₆₀fullerenes affected mainly the response to vasorelaxation in young apoE^-/-mice, whereas the vasomotor dysfunction in old apoE^-/-mice with more advanced atherosclerosis was less affected by acute C₆₀fullerene treatment. These findings represent an important step in the hazard characterization of C₆₀fullerenes by showing that intraperitoneal administration is associated with a moderate decrease in the vascular function of mice with atherosclerosis.</p

Modest effect on plaque progression and vasodilatory function in atherosclerosis-prone mice exposed to nanosized TiO2

<p>Abstract</p> <p>Background</p> <p>There is growing evidence that exposure to small size particulate matter increases the risk of developing cardiovascular disease.</p> <p>Methods</p> <p>We investigated plaque progression and vasodilatory function in apolipoprotein E knockout (<it>ApoE</it>^-/-) mice exposed to TiO₂. <it>ApoE</it>^-/-mice were intratracheally instilled (0.5 mg/kg bodyweight) with rutile fine TiO₂(fTiO₂, 288 nm), photocatalytic 92/8 anatase/rutile TiO₂(pTiO₂, 12 nm), or rutile nano TiO₂(nTiO₂, 21.6 nm) at 26 and 2 hours before measurement of vasodilatory function in aorta segments mounted in myographs. The progression of atherosclerotic plaques in aorta was assessed in mice exposed to nanosized TiO₂(0.5 mg/kg bodyweight) once a week for 4 weeks. We measured mRNA levels of <it>Mcp-1</it>, <it>Mip-2</it>, <it>Vcam-1</it>, <it>Icam-1 </it>and <it>Vegf </it>in lung tissue to assess pulmonary inflammation and vascular function. TiO₂-induced alterations in nitric oxide (NO) production were assessed in human umbilical vein endothelial cells (HUVECs).</p> <p>Results</p> <p>The exposure to nTiO₂was associated with a modest increase in plaque progression in aorta, whereas there were unaltered vasodilatory function and expression levels of <it>Mcp-1</it>, <it>Mip-2</it>, <it>Vcam-1</it>, <it>Icam-1 </it>and <it>Vegf </it>in lung tissue. The <it>ApoE^-/-</it>mice exposed to fine and photocatalytic TiO₂had unaltered vasodilatory function and lung tissue inflammatory gene expression. The unaltered NO-dependent vasodilatory function was supported by observations in HUVECs where the NO production was only increased by exposure to nTiO₂.</p> <p>Conclusion</p> <p>Repeated exposure to nanosized TiO₂particles was associated with modest plaque progression in <it>ApoE^-/-</it>mice. There were no associations between the pulmonary TiO₂exposure and inflammation or vasodilatory dysfunction.</p