Targeted nanomedicine builds on the concept that nanoparticles can be directed to specific tissues while remaining inert to others organs. Many studies have been performed on the synthesis and cellular interactions of core− shell nanoparticles, in which a functional inorganic core is coated with a biocompatible polymer layer that should reduce nonspecific uptake and cytotoxicity. However, work is lacking that relates structural parameters of the core−shell structure and colloidal properties directly to interactions with cell membranes and further correlates these interactions to cell uptake. We have synthesized monodisperse (SD < 10%), single-crystalline, and superparamagnetic iron oxide nanoparticles (SPION) of different core size (3−8 nm) that are densely grafted with nitrodopamine-poly(ethylene glycol) (NDA-PEG(5 kDa)) brushes. We investigated the interactions of the PEGylated SPION with biomimetic membranes and cancer and kidney cells. It is shown that a dense homogeneous PEG shell suppresses membrane interactions and cell uptake but that nanoparticle curvature can influence membrane interactions for similarly grafted nanoparticles. Weak adsorption to anionic lipid membranes is shown to correlate with eukaryote cell uptake and is attributed to double-layer interactions without direct membrane penetration. This attraction is strongly suppressed during physiological conditions and leads to unprecedented low cell uptake and full cell viability when compared to those of traditional dextran-coated SPION. Less curved (larger core) PEGylated SPION show weaker membrane adsorption and lower cell uptake due to effectively denser shells. These results provide a better understanding of design criteria for core−shell nanoparticles in terms of avoiding nonspecific uptake by cells, reducing toxicity, and increasing circulation time.

Despite the abundant literature on the adverse effects of Bisphenol A (BPA) as endocrine disruptor, its toxicity mechanisms are still poorly understood. We present here a study of its effects on the zebrafish eleutheroembryo transcriptome at concentrations ranging from 0.1 to 4 mg L, this latter representing the lowest observed effect concentration (LOEC) found in our study at three different macroscopical endpoints (survival, hatching and swim bladder inflation). Multivariate data analysis methods identified both monotonic and bi-phasic patterns of dose-dependent responses. Functional analyses of genes affected by BPA exposure suggest an interaction of BPA with different signaling pathways, being the estrogenic and retinoid receptors two likely targets. In addition, we identified an apparently unrelated inhibitory effect on, among others, visual function genes. We interpret our data as the result of a sum of underlying, independent molecular mechanisms occurring simultaneously at the exposed animals, well below the macroscopic LOEC, but related to at least some of the observed morphological alterations, particularly in eye size and yolk sac resorption. Our data supports the idea that the physiological effects of BPA cannot be only explained by its rather weak interaction with the estrogen receptor, and that multivariate analyses are required to analyze the effects of toxicants like BPA, which interact with different cellular targets producing complex phenotypes.

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The aim of this study is to compare the azole synergy across an insect, Chironomus riparius, and a crustacean species, Daphnia magna. We use a combination of in vivo measurements of cytochrome P450 monooxygenase (CYP) biotransformation potential and toxicokinetic (TK) and toxicodynamic (TD) modeling to understand the mechanism behind the synergy of two azole fungicides: the imidazole prochloraz and the triazole propiconazole on the pyrethroid insecticide α-cypermethrin. For both species, the synergistic effect of prochloraz was well-described by its effect on in vivo CYP activity, which corresponded to the biotransformation rate of the TK model parameterized on the survival data of the mixture experiment. For propiconazole, however, there were 100-fold and 50-fold differences between the 50% effect concentration of in vivo CYP activity and the modeled biotransformation rate for C. riparius and D. magna, respectively. Propiconazole, therefore, seems to induce synergy through a mechanism that cannot be quantified solely by the CYP activity assay used in this study in either of the two species. We discuss the differences between prochloraz and propiconazole as synergists across the two species in the light of the type and time dynamics of affected biotransformation processes.

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