Particle Uptake

Some types of particles appear to be able to produce genotoxicity. At least in vitro, mineral fibers can cause DNA damage by direct physical interference with the mitotic apparatus or adhesion to individual chromosomes, with resulting 

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Particles that catalyze the formation of AOS can also cause oxidation of individual bases, as well as DNA strand breaks, if the particle enters the nucleus and is in close approximation to chromosomes. For the most part, this process is mediated by the iron-catalyzed formation of highly reactive species, such as hydroxyl radical, either using the surface iron on the particle itself as a Fenton catalyst, or using surface iron leached from the particle into the cytosol, where it acts in a fashion similar to a mobile source of hydroxyl radical formation (5,6). 

Mineral fibers, particularly asbestos, can activate protein kinase C and increase expression of ornithine decarboxylase, the proto-oncogenes, c-fos, and c-jun (18-20), and the nuclear transcription factor, NF-kB (21). All these events are associated with cell proliferation and, potentially, with neoplastic transformation. Recently, Zanella et al. (22) have shown that asbestos activates the mitosis-associated kinase (MAP) system, apparently through interaction with the epidermal growth factor receptor, probably implying that some of these events are mediated by signal transduction pathways that start on the cell surface, rather than by fiber uptake, although this point needs to be directly examined. 

Radioactive particles (e g., Po derived from cigarette smoke) that are translocated through epithelial cells (see later discussion) to the interstitium may come to lodge under the epithelial basement membrane and from there deliver carcinogenic doses of radiation to the overlying epithelium. It has been proposed that this process plays an important role in cigarette smoke carcinogenesis (28,29). 

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Foged C, Brodin B, Frokjaer S et al (2005) Particle size and surface charge affect particle uptake by human dendritic cells in an in vitro model. Int J Pharm 298 315-322... 

Thiele L, Rothen-Rutishauser B, Jilek S et al (2001) Evaluation of particle uptake in human blood monocyte-derived cells in vitro. Does phagocytosis activity of dendritic cells measure up with macrophages J Control Release 76 59-71... 

Surface properties of particles and size have a great impact on particle uptake. In vitro studies performed by des Rieux et al. (2005) in co-cultures showed that the number of transcytosed nanoparticles having a diameter of 200 nm was seven times higher than that of 500 nm. Desai et al. (1996) studied the uptake by the Peyer s patch tissue of different-sized polylactic polyglycolic acid (50 50) copolymer nano- and microparticles concluding that the efficiency of uptake of 100-nm size particles by the intestinal tissue was 15-250-fold higher compared... 

Florence, A. T., A. M. Hillery, et al. (1995). Nanoparticles as carriers for oral peptide absorption studies on particle uptake and fate. J Control Release 36 39-46. 

Jani PU, McCarthy DE, Florence AT. Titanium dioxide (rutile) particle uptake from the rat GI tract and translocation to systemic organs after oral administration. Int ] Pharm 1994 105(May 2) 157-168. 

Silver DL,Nan W, Xiao X, Tall AR. 2001. HDL particle uptake mediated by SR-BI results in selective sorting of HDL cholesterol from protein and polarized cholesterol secretion. J. Biol. Chem. 276 25287-93... 

When talking about the NM dose, one has to make a distinction between three dose metrics (1) the administered dose (particle mass, number, or surface area administered per volume media at the onset of an experiment), (2) the delivered dose (particle mass, number, or surface area to reach the cell monolayer via diffusion and sedimentation over the duration of an experiment), and (3) the cellular dose (particle mass, number, or surface area internalized by the cells during the experiment). The determination of the cellular and delivered dose of NMs is essential for accurate interpretation of results derived from in vitro particle-cell interaction studies (e.g., particle uptake, cytotoxicity, biokinetic studies) [36], Using two different cell culture configurations, upright and inverted, Cho et al. [37] have recendy shown that the uptake of NPs is gready sensitive to the position in which cells are cultured and strongly... 

Florence AT. Oral particle uptake irrefutable and significant. J Hiarm Sci (in press). 

Fig. 3 Different entry pathways into the cell. Lipid particles can be taken up either through clathri n or caveoUn dependent or independent pathways. Another possibility of lipid particle uptake is phagocytosis...

R3. Roberts, J., and Quastel, J. H., Particle uptake by polymorphonuclear leucocytes and Ehrlich ascitescarcinoma cells. Biochem. J. 89, 150-156 (1963). 

The use of nanoparticles for oral appHca-tion is an intensively studied concept for the delivery of poorly soluble drugs, as discussed above. Particle uptake has been known for more than 50 years via M-cells as specialized phagocytic enterocytes, but also via lymphoid tissue and normal intestinal enterocytes [75, 76]. The kinetics of particle uptake and translocation depend on biopharmaceutical parameters like accessibility through the mucus and contact with the enterocytes, as well as on the physical properties of the particle like its size, particle charge, surfactant coating and, sometimes, targeting devices. 

Surprisingly a number of epidemiology studies in the early nineties showed associations between ambient particulate matter and increases in cardiac-related deaths and/or morbidity indicators and that the risk of PM-related cardiac effects may be so great or greater than those attributed to respiratory causes. These effects appear to be induced via direct particle uptake into the blood and/or via mediation by the nervous system. Such effects may be especially deleterious to individuals... 

It could be shown that PBCA particles are also internalized by HeLa, Jurkat, and mesenchymal stem cells (MSCs) however, the cellular uptake kinetics are different for HeLa and Jurkat cells (see Fig. 6) [35, 36]. While the particle size has a significant impact on particle uptake in HeLa cells, Jurkat cells are more sensitive towards surface functionalization. Especially the methoxypolyfethylene glycol) (MePEG)-fimctionalized particles are internalized to a lesser extent than the rest of the investigated particles (non-functionalized, phenylalanine-functionalized). 

Another major factor affecting the particle uptake is the nature of the material used to prepare the particles. Uptake of nanoparticles prepared from hydrophobic polymers seems to be higher than that from particles with more hydrophilic surfaces. Microspheres composed of polystyrene, poly(methylmethacrylate), poly(hydroxybutyrate), poly(D,L-lactide), poly(L-lactide), and poly(o,L-lactide-co-glycolide) were absorbed into the Peyer s patches of the small intestine, whereas those composed of ethyl cellulose, cellulose acetate hydrogen phthalate, and cellulose triacetate were not absorbed. Residual poly(vinyl alcohol) in the surface of PLGA nanoparticles significantly reduced the intercellular uptake, in spite of the smaller particle size." Similarly, poloxamer coating of... 

Is particle uptake sufficient enough to achieve therapeutic effectiveness ... 

Shakweh, M. et al. Particle uptake by Payer s patches A pathway for drug and vaccine delivery. Expert Opin. Drug Deliv., 1, 141, 2004. 

Particle uptake by Peyer s patches a pathway for drug and vaccine delivery. Review Shakweh et al. (2004)... 

TABLE 6.4. Experimental Conditions for Sinigle-Particle Uptake Measurements ... 

TABLE 6.5. Diffusivities Derived from Single-Particle Uptake Experiments... 

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