ABSTRACT
The blood-brain barrier (BBB) constitutes an effective barrier to exclude undesirable and/or toxic substances in the bloodstream from entering the central nervous system, including the brain. In this context, for targeting therapeutic agents to the brain, one needs to device mechanism(s) whereby this restriction of the BBB is overcome or by-passed. Consequently, various studies on employing nanoparticles to assist with drug delivery or delivery of genetic material to advance gene therapy have concluded that nanoparticles can cross the BBB [9, 10]. For example, Kim et al. [9] synthesized silica-overcoated magnetic nanoparticles containing rhodamine B isothiocyanate within a silica shell of controllable thickness (MNPs@SiO2(RITC)), employing particles with 50 nm
thickness. They administered those particles intraperitoneally into mice for four weeks and were able to detect the nanoparticles in the brains of those mice. Their study [9] clearly demonstrated that such nanoparticles can penetrate the BBB. Nanoparticles have also been employed to achieve neuron-
specific delivery of genetic material to advance gene therapy of various neurological disorders. For example, Zang et al. [11] employed 85 nm PEGylated immunoliposome (containing antibodies to the rat transferrin receptor) to deliver tyrosine hydroxylase (TH) expression plasmid to normalize TH activity in the striatum in a rat model of experimental parkinsonism induced by 6-hydroxydopamine. Their results demonstrated that intravenously administered immunoliposomes containing the TH expression plasmid could cross the BBB giving rise to increased striatal TH activity in the TH-transfected rats [11]. Thus, their findings suggested that the immunoliposomes crossed the BBB via the transvascular route [11]. In addition to the transvascular route, nanoparticles can also cross the BBB after they have induced alterations in BBB permeability and induced cerebral edema [10]. 38.3 Toxicity of Silicon Dioxide Nanoparticles in
Mammalian Neural CellsThe toxicity of silicon dioxide nanoparticles in mammalian neural cells is discussed below from three perspectives: (i) environmental health impact of exposure to silicon dioxide nanoparticles, (ii) toxicity of the nanoparticles in mammalian neural cells in vivo, and (iii) toxicity of the nanoparticles in mammalian neural cells in vitro. 38.3.1 Environmental Health Impact of Exposure to
As has already been alluded to above, the ever-increasing use of silicon dioxide, including a range of its particles sizes, in cosmetics, food, drug formulations, and numerous other industrial applications [2, 3, 12] has raised some concerns regarding the environmental health impact of human exposure to silicon dioxide
particles, especially nanoparticles [12]. Because nanoparticles, including silicon dioxide nanoparticles, can cross the BBB (see above), their accumulation in significant quantities in the central nervous system can induce deleterious effects on neural cells, thereby disturbing the normal functions of such cells and even inducing neurodegeneration. The findings of three early studies provide some support for the notion that accumulation of silicon dioxide nanoparticles in the brain could lead to neurodegeneration [13-15]. Silica micro-and nanoparticles, when introduced into the brains of rats and mice, induced inflammatory responses in brain astrocytes and macrophages and degeneration of axons and axon terminals adjacent to the astrocytes [13]. Silicon and aluminum were noted to be co-localized in the central region of senile plaque cores in the cortex of patients with senile dementia of the Alzheimer type [14]. Moreover, the accumulated silicon and aluminum appeared to be found, at least in part, in lipofuscin granules in the brains of patients who died with Alzheimer’s disease [15]. 38.3.2 In vivo Toxicity of Silicon Dioxide Nanoparticles
in Mammalian Neural CellsThere have been very few studies on the toxicity of silicon dioxide nanoparticles in vivo on mammalian neural cells. Nevertheless, the results of the few studies are quite revealing and allow us to make two tentative generalizations. First, silicon dioxide nanoparticles can cross the BBB; one consequence of such particles being able to cross the BBB is that they could, at least potentially, exert undesirable effects on neural cells in the central nervous system. Second, most of the toxic effects of silicon nanoparticles in vivo on neural cells are similar to, if not identical with, the effects of such nanoparticles noted in neural cells in vitro (see below). Thus, this generalization points to the utility of employing neural cell models in vitro to screen for the toxicity of various types of silicon dioxide nanoparticles and the importance of employing such models to elucidate the cellular and molecular mechanisms underlying the cytotoxicity of silicon dioxide nanoparticles. Nevertheless, it is noteworthy that the cytotoxicity of these nanoparticles in neural cells cannot be easily and readily investigated employing animal models in studies in vivo. We will
briefly discuss how the findings of the few studies on toxicity of silicon dioxide nanoparticles on neural cells in vivo have led us to formulate the two generalizations above.In their study to investigate toxicity and tissue distribution of silica-overcoated magnetic nanoparticles in mice, Kim et al. [9] synthesized silica-overcoated magnetic nanoparticles containing rhodamine B isothiocyanate within a silica shell of controllable thickness (MNPs@SiO2(RITC)). They employed MNPs@SiO2(RITC) with 50 nm thickness and administered those particles intraperitoneally into mice for four weeks and were able to detect the nanoparticles in the brains of those mice. Furthermore, using an immunocytochemical approach and employing the dorsal cochlear nucleus as a representative example of whole brain localization, they were able to show that MNPs@SiO2(RITC) colocalized with a well-characterized neuronal marker, NeuN. Based on their observations, Kim et al. concluded that the silica nanoparticles (MNPs@SiO2(RITC)) could cross the BBB, enter neurons, but do not alter the permeability of the BBB [9]. Nevertheless, they did not detect any gross abnormal histopathological lesions in several organs, including brain, kidney, liver, testis, uterus, lung, heart, and spleen, in mice four weeks after intraperitoneally injecting MNPs@SiO2(RITC) into the mice at 25, 50, or 100 mg/kg [9]. Consequently, Kim et al. [9] concluded such silica nanoparticles can penetrate the BBB and enter neurons without apparently altering their normal function, suggesting that the silica-overcoated nanoparticles at the doses employed were apparently not toxic to neurons. The findings and conclusions of Kim et al. [9] are in sharp contrasts with those of a more recent study by Wu et al. [16].
