Biodistribution and toxicity of pegylated single wall carbon nanotubes in pregnant mice

Abstract

BackgroundSingle wall carbon nanotubes (SWCNTs) are considered promising nanoparticles for industrial and biomedical applications; however their potential toxicity in several biological systems, including the feto-placental unit, has been demonstrated. Functionalization of SWCNTs with polyethylene glycol chains (PEG-SWCNTs) dramatically reduces their toxicity, and for this reason PEG-SWCNTs are candidates for biomedical applications. However, no data are available on their safety for the developing embryo, in spite of the clinical and social relevance of this topic. The purpose of this study is therefore to investigate the safety of PEG-SWCNTs for their use as biomedical carriers in pregnancy.MethodsFor toxicological studies, amino-functionalized PEG-SWCNT were intravenously injected in CD1 pregnant mice at different doses (range 0.1-30 μg/mouse), in single or multiple administrations. For biodistribution studies, fluorescently labeled PEG-SWCNTs were obtained by acylation of terminal PEG amino groups with near infrared emitting fluorochromes (PEG-SWCNT-750) and injected at the dosage of 10 μg/mouse, at either day 5.5 (when the placenta is still developing) or day 14.5 of gestation (when the maturation of the placenta is complete).ResultsWe found no adverse effects both on embryos and dams up to the dose of 10 μg/mouse. At the dose of 30 μg/mouse, occasional teratogenic effects, associated with placental damage, were detected both when administered as a single bolus (1 out of 10 dams; 1 malformed embryo) or as multiple doses (2 out of 10 dams; 5 malformed embryos). The difference in the prevalence of dams with malformed embryos between the 30 μg exposed group and controls approached the statistical significance (p = 0.06). Hepatic damage in dams was seen only in the multiple exposure group (4 out of 10; p = 0.04 when compared with the single exposure group or controls). PEG-SWCNT-750 reached the conceptus when administered early in pregnancy. At later stages, PEG-SWCNT-750 were detected in the placenta and the yolk sac, but not in the embryo.ConclusionsPEG-SWCNTs may cause occasional teratogenic effects in mice beyond a threshold dose. Such effect might depend on their ability to reach the feto-placenta unit. Although not automatically transferable to humans, these data should be considered if exposing women during pregnancy.

Nanosafety forum for young scientists: a meeting report

“…A lack of toxicity was reported also by L. Vecchione (Department of Biomedicine and Prevention, University of Rome Tor Vergata), who, in contrast with previous data of acute exposure to nanoparticles during pregnancy (16,17), did not observe any effect on the reproductive ability of female mice after chronic exposure before pregnancy to low dose ZnO and TiO 2 nanoparticles.…”

Embryonic Toxicity of Nanoparticles

“…Similarly, SWCNT fused with PEG chains caused occasional teratogenic effects only when using high concentrations in the mouse [Campagnolo et al, 2013]. As embryonic malformations arise when using concentrations beyond a threshold dose, then only low concentrations of nanotubes should be used for potential therapeutic treatments.…”

<div>Long-term intravenous administration of carboxylated single-walled carbon nanotubes induces persistent accumulation in the lungs and pulmonary fibrosis via the nuclear factor-kappa B pathway</div>

“…24 Furthermore, intravenous exposure to high doses of CNTs might cause reproductive toxicity and embryotoxicity. 25,26 These controversial results are suggested to be associated with varied physicochemical properties of CNTs and exposure doses and time that may influence their toxicity profile. For example, metallic SWNTs induced more ROS generation than semiconducting SWNTs in several kinds of cells in vitro, 27,28 and oxidized SWNTs caused a higher percentage of early miscarriages and fetal malformations than pristine SWNTs in female mice.…”