Multifunctional nanoparticles for real-time evaluation of toxicity during fetal development

Abstract

Increasing production of nanomaterials in industrial quantities has led to public health concerns regarding exposure, particularly among pregnant women and developing fetuses. Information regarding the barrier capacity of the placenta for various nanomaterials is limited due to challenges working with ex vivo human placentas or in vivo animal models. To facilitate real-time in vivo imaging of placental transport, we have developed a novel, multifunctional nanoparticle, based on a core of mesoporous silica nanoparticles (MSN), and functionalized for magnetic resonance imaging (MRI), ultrasound, and fluorescent microscopy. Our MSN particles were tested as a tracking method for harmful and toxic nanomaterials. In gravid mice, intravenous injections of MSN were administered in the maternal circulation in early gestation (day 9) and late gestation (day 14). MRI and ultrasound were used to track the MSN following the injections. Changes in contrast relative to control mice indicated that MSN were observed in the embryos of mice following early gestation injections, while MSN were excluded from the embryo by the placenta following late gestation injections. The timing of transplacental barrier porosity is consistent with the notion that in mice there is a progressive increasing segregation by the placenta in later gestation. In addition, built-in physico-chemical properties of our MSN may present options for the therapeutic treatment of embryonic exposure. For example, if preventive measures such as detoxification of harmful compounds are implemented, the particle size and exposure timing can be tailored to selectively distribute to the maternal side of the trophoblast or delivered to the fetus.

Translocation of (ultra)fine particles and nanoparticles across the placenta; a systematic review on the evidence of in vitro, ex vivo, and in vivo studies

“…Other studies reported a time-dependent accumulation of Ag NPs, CeO 2 NPs, and fullerenes as they found that the fetal NP concentration increased over time, reached a peak, and then declined [ 54 , 67 , 87 ]. Moreover, critical exposure windows during gestation were evaluated by defining changes in particle transfer after varying the day of NP exposure [ 60 , 61 , 70 , 71 , 87 ]. Pregnant rats were divided into five groups and differently exposed with radioactively-labeled fullerenes ( 14 C(C60)) via single i.v.…”

“…SiO 2 NPs reach the fetal bloodstream and bioaccumulate in both embryos and fetuses. [ 71 ] C57Bl/6 mice 11 MMSNPs/ gadolinium oxide-core and TFP 100–200 b i.v./ 0 or 1 mg/mouse/ GD7–9 or 14–15 d MRI and ultrasound imaging / SiO 2 NPs observed in embryos of mice following early gestation injections while being excluded from the embryo by the placenta following late gestation injection. [ 72 ] CD-1 mice 44 Pt NPs 20.9 ± 11.4 a oral/ 0, 0.25, 0.5, or 1 mg/kg/ 14 days before mating-PND4 g ICP-MS / No detection of Pt NPs in pups of mice orally exposed before, during, and after gestation.…”

“…For quantitative visualization of non-fluorescent NPs in biological systems, fluorescent labeling (e.g. , using fluorescein isothiocyanate [ 71 ] or rhodamine [ 24 , 25 ]) can be employed followed by fluorescence detection methods. Melnik et al used the radioactive silver isotope 110m Ag to label and track PVP-stabilized 34.9 nm Ag NPs with gamma spectrometry, showing their accumulation in placental and fetal tissue following oral administration to pregnant mice on GD20 [ 53 ].…”

“…A time-dependent transfer was observed as SiO 2 NPs were only detected in the pups following maternal i.v. injection during early gestation (GD9) and not late gestation (GD14) [ 71 ]. Other quantitative analysis methods are mainly based on elemental analysis.…”

“…This supports the finding that the placenta is not an impenetrable barrier, as already confirmed for other xenobiotics such as drugs and alcohol [ 131 ]. In animal models, transplacental passage has been reported for Ag NPs [ 47 – 54 ], Al 2 O 3 NPs [ 44 ], Au NPs [ 57 , 59 – 61 ], CeO 2 NPs [ 67 ], DEP [ 91 ], QDs [ 62 ], SiO 2 NPs [ 70 , 71 , 73 , 74 ], TiO 2 NPs [ 73 , 75 , 76 , 78 , 80 , 81 ], ZnO NPs [ 83 – 85 ], ZrO 2 NPs [ 86 ], Fe 2 O 3 NPs [ 69 ], C60 fullerenes [ 87 ], PGMA NPs [ 89 ], and PS NPs [ 27 ]. Among these particles, only Ag NPs [ 37 ], Au NPs [ 31 , 38 ], and PS NPs [ 40 – 43 ] showed transplacental transfer in an ex vivo perfusion model, whereas SiO 2 NPs [ 25 ] and TiO 2 NPs [ 34 ] were retained in the placental tissue.…”