In Vitro Tolerability

Cell cultures are increasingly used to assess the potential toxic effects of drugs, excipients, but also delivery systems such as nanoparticles. A rough measure of cytotoxicity is the viability of cells. Of course, cell cultures cannot imitate special elimination mechanisms in the living organism, but at least they provide a general impression of cellular toler-ability. In vitro determination of cell viability reflected very well the differences between relatively cytotoxic polyalkyl-cyanoacrylate nanoparticles and much better tolerated poly-lactic acid (PLA) and PLA/PGA nanoparticles. The EC50 (effective concentration leading to a 50% cell death) was about 20 ¡xg/mL for polymethylalkylcyanoacrylate nanoparticles [53]. Concentrations of about 0.5% were well tolerated in the case of PLA nanoparticles, but the copolymer particles with polyglycolic acid led to 100% cell death [54]. An even better tolerability was found for SLN dispersions; concentrations of 10% in the cell culture led only to a reduction of viability to about 80% [54]. A similar good tolerability can be assumed for NLCs, especially when considering that a part of the solid glycerides of SLNs is replaced by even better tolerated oils, for example, MCT used in parenteral nutrition. Cell culture studies of emulsions for parenteral nutrition showed even less cytotoxic-ity compared to lipid nanoparticles (viability of peritoneal macrophages after 20 h of in vitro culture: emulsion = 97%, SLN = 82-75%) [55].

Of course, cell viability is a very crude measure to assess cytotoxicity. To obtain a deeper insight, it is more appropriate to determine the induction of production of Interleukin 6 and 12, as well as TNF-a. Such cytotoxic effects on the molecular level can lead to a serious disturbance in the living organism. In the last few years, systematic studies were performed to measure these parameters after incubation, with SLNs being composed of different lipids, and also produced from different surfactants [55]. In addition, the size effect on the cytotoxicity was also investigated. These results can be summarized as follows: none of the investigated lipids led to a serious increase in the production of Interleukins or TNF-a when using well-tolerated surfactants (Fig. 6). Again, a similar or even better tolerability can be expected for NLCs.

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