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Chemical and Colloidal Stability of Carboxylated Core-Shell Magnetite Nanoparticles Designed for Biomedical Applications

Despite the large efforts to prepare super paramagnetic iron oxide nanoparticles (MNPs) for biomedical applications, the number of FDA or EMA approved formulations is few. It is not known commonly that the approved formulations in many instances have already been withdrawn or discontinued by the producers; at present, hardly any approved formulations are produced and marketed. Literature survey reveals that there is a lack for a commonly accepted physicochemical practice in designing and qualifying formulations before they enter in vitro and in vivo biological testing. Such a standard procedure would exclude inadequate formulations from clinical trials thus improving their outcome. Here we present a straightforward route to assess eligibility of carboxylated MNPs for biomedical tests applied for a series of our core-shell products, i.e., citric acid, gallic acid, poly(acrylic acid) and poly(acrylic acid-co-maleic acid) coated MNPs. The discussion is based on physicochemical studies (carboxylate adsorption/desorption, FTIR-ATR, iron dissolution, zeta potential, particle size, coagulation kinetics and magnetization measurements) and involves in vitro and in vivo tests. Our procedure can serve as an example to construct adequate physico-chemical selection strategies for preparation of other types of core-shell nanoparticles as well.

Nervous system effects in rats on subacute exposure by lead-containing nanoparticles via the airways

Context and objective: Lead (Pb) is a heavy metal harmful for human health and environment. From leaded gasoline (still used in certain countries), and in Pb processing and reprocessing industries, airborne particles are emitted which can be inhaled. In such exposure, the size of particles entering the airways is crucial. The nervous system is a primary target for Pb, and consequences like occupational neuropathy and delayed mental development of children are well-known. The aim of this work was to investigate the neurotoxicity of Pb nanoparticles (NPs) applied into the airways of rats. Methods: Nano-sized lead oxide particles (mean diameter ca. 20 nm) were suspended in distilled water and instilled into the trachea of adult male Wistar rats (in doses equivalent to 2 and 4 mg/kg Pb), 5 times a week for 3 and 6 weeks. At the end, open field motility was tested, then central and peripheral nervous activity was recorded in urethane anesthesia. Results and conclusion: The treated rats’ body weight gain was significantly lower than that of the controls from the 3rd week onwards, and the weight of their lungs was significantly increased. Horizontal motility increased while vertical motility decreased. Spontaneous cortical activity was shifted to higher frequencies. The somatosensory cortical evoked potential showed increased latency and decreased frequency-following ability, and similar alterations were seen in the tail nerve. Significant Pb deposition was measured in blood, brain, lung and liver samples of the treated rats. The experiments performed seem to constitute an adequate model of the human effects of inhaled Pb NPs.

Consequences of subacute intratracheal exposure of rats to cadmium oxide nanoparticles: Electrophysiological and toxicological effects

Cadmium (Cd) is a metal used in various industrial applications, thereby causing exposure to Cd-containing fumes. The submicron-sized particles in the fumes represent an extra risk due to their high mobility within the organism and high surface area. Toxicity of Cd on the liver, kidney and bones is well known, but there are less data on its neurotoxicity. Here, male Wistar rats were treated for 3 and 6 weeks by intratracheal instillation of cadmium oxide nanosuspension. The body weight gain in treated rats was significantly decreased, and in the rats treated with high dose (0.4 mg/kg Cd daily), there was a significant increase in the weight of lungs and thymus. In this group, the spectrum of spontaneous cortical electrical activity was shifted to higher frequencies, the latency of sensory-evoked potentials was lengthened, and the frequency following ability of the somatosensory evoked potential was impaired—even without detectable Cd deposition in the brain. The data support the role of the nano-sized Cd in the causation of nervous system damage and show the possibility of modeling human neurotoxic damage in rats.

Nervous system effects of dissolved and nanoparticulate cadmium in rats in subacute exposure

Cadmium, a toxic heavy metal with various applications in technology, can affect people both by environmental (foodborne) and occupational (inhalation) exposure and can cause nervous system damage. To model this, rats were subacutely treated either with CdCl2 solution per os (3.0 mg kg−1 b.w.) or nanoparticulate CdO2 (particle size ca 65 nm) by intratracheal instillation (0.04 mg kg−1 b.w.) alone or in sequential combination. Nervous system effects were observed at different levels of function (open field behavior, cortical electrical activity, nerve action potential) and some general toxicological indicators were also measured. Three weeks of oral plus one week of intratracheal exposure caused significant reduction of body weight gain and open field motility. Lengthening of latency of sensory evoked potentials, observed in all treated rats, was also the most significant in the group receiving oral plus intratracheal treatment. Conduction velocity of the tail nerve was likewise decreased in all treated groups. Several of the effects pointed to a potentiating interaction between the two forms of Cd. Modeling environmental and occupational Cd exposure by oral and intratracheal application in rats was feasible, with results suggesting serious negative health effects in humans suffering such a combined exposure.

Repeated-dose toxicity of common ragweed on rats

Ambrosia artemisiifolia L. is an invasive species with highly allergenic pollens. Ragweed originates from North America, but it also occurs and is spreading in Europe, causing seasonal allergic rhinitis for millions of people. Recently, the herb of A. artemisiifolia has gained popularity as medicinal plant and food. The effects of its long-term intake are unknown; there are no toxicological data to support the safe use of this plant. The aim of our study was to assess the repeated dose toxicity of A. artemisiifolia on animals. Ragweed puree was administered in low dose (500 mg/kg b. w.) and high dose (1000 mg/kg b. w.) to male Wistar rats according to 407 OECD Guidelines for the Testing of Chemicals. Clinical symptoms, various blood chemical parameters, body weight and organ weights of the rats were measured. Reduced liver function enzymes (AST, ALT), reduced triglyceride level in the low dose and increased carbamide level in the high dose group were observed. The weight of the liver relative to body weight was significantly reduced in both groups, while the brain weight relative to body weight was significantly elevated in both groups. According to our results, the repeated use of ragweed resulted in toxic effects in rats and these results question the safety of long-term human consumption of common ragweed.

A pilot study with simultaneous recording of changes in motility and cortical electrical activity of rats during four weeks of oral manganese exposure.

Manganese as an environmental neurotoxicant can cause oral exposure. Six rats were equipped with a connector “crown”, allowing repeated recording of electrocorticogram (ECoG) with simultaneous recording of motor activity in an open field box. Weekly one 30-min recording session was held, and after two control sessions, four of the six rats had 2.5 mg/ml manganese chloride in their drinking water. The treated rats showed higher motility during the exposure period than the untreated ones; and substantially decreased total ECoG power without marked change the spectrum. The changes of both motility and ECoG were correlated to the individual brain Mn levels, and the activity decrease during a session was correlated to the total ECoG power. These effects can be likened to early adult manganism and to symptoms of children exposed to Mn via drinking water. Repeated simultaneous recording of open field motility and spontaneous cortical activity seems suitable to detect early electrophysiological and behavioral effects of an oral neurotoxic exposure.