However, animals treated with PFD-filled PLGA microcapsules exper

However, animals treated with PFD-filled PLGA microcapsules experienced a mild metabolic acidosis (Fig. S2) corresponding to the data

of Sedova et al. describing the same phenomenon after infusion of a PFC-containing emulsion [60]. Probably lactate formation in muscle tissue increases due to transient hypotension and reduced number of perfused vessels of sinusoids. This can entail an undersupply of affected tissue areas with oxygen triggering anaerobic glycolysis [61]. The increase in enzyme activities in plasma, such as LDH as a general marker of cell injury and CK as a marker for muscle cell injury, should further support the assumption of cellular damage (Fig. 3C and D). An increased LDH level was also described after contact Fludarabine chemical structure of silica nanoparticles with human endothelial cells and after pulmonary exposition of rats to polystyrene

particles [62]. In contrast, intravenous injection of nanoporous silicon microparticles provoked only a mild increase in LDH plasma activity [63]. As these data were obtained 24 h post injection of microparticles, LBH589 they differ from the acute response (only 4 h post infusion of PLGA microcapsules) monitored in this study as expected. Reduced perfusion and hypoxia also damaged liver and spleen tissue. Pathological tissue alteration and increase in plasma activities of liver tissue-associated enzymes such as ALAT and ASAT after infusion of PFD-filled PLGA microparticles further emphasize liver damage (Fig. 2 and Fig. 3). This matches data on PFC-containing emulsions describing a transient increase of plasma transaminase activities because of accumulation of emulsion droplets in Kupffer cells [64]. The conventional in vivo degradation of PLGA to lactic and glycolic acid in the presence of oxygen [ 65], with all metabolites entering the tricarboxylic acid cycle (further degradation into H2O and

CO2) [ 66] or, the alternative elimination of glycolic acid via the kidney [ 67] certainly were not the reason for the observed acidosis, as PLGA is attributed Carnitine palmitoyltransferase II with an in vivo degradation time of 50–60 days [ 68]. Although this degradation process of PLGA is primarily a hydrolytic process (drivable by enzymes, such as trypsin, but not dependent on their presence [ 69]) contact with blood (not containing the relevant enzymes) does not enhance the degradation of PLGA microcapsules. In line with this, degradation studies with PEG-PLGA capsules show a decay rate of only about 15% 1–3 h after intravenous administration [ 70] and studies with PLGA films describe a drop in pH only after an in vitro degradation period of 30 days [ 71]. Hence, the impact of these degradation mechanisms becomes more important in a later phase and thus, cannot explain the observed mild, metabolic acidosis. Generally, the infusion of high quantities of PFD-filled PLGA microcapsules was tolerated as all animals survived the selected observation period.

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