Toxicity and Tissue Distribution

As discussed before, nanoparticles generally are captured by the MPS macrophages after intravenous administration. However, phagocytic stimuli induce macrophages to secrete a large number of substances, including eicosanoids, active oxygen metabolites from the respiratory burst, and cytokines that may have a strong influence on the inflammatory response. These substances are required for the elimination of pathogenic organisms but are unnecessary and potentially deleterious when the ingested particles are inert and nonpathogenic. The acute phase response may result in impaired defense against infection, hypersensitivity reactions and other unknown undesirable effects. It has been shown that single intravenous injection of PACA or PLA nanoparticles led to an acute inflammatory response, characterized by the increase of serum alpha 1-acid glycoprotein (AGP) levels, an acute phase protein in rats [111]. Now, since the surface coating of the nanoparticles with hydrophilic polymers results in a significant modification of the body distribution profile, it is evident that, as a consequence, it may influence the toxicity of the polymer-drug entity, too. Indeed, altered pharmacokinetic and disposition of the drug should induce novel modalities of cells, tissues, or receptor exposures, as well as novel drug metabolism and drug interactions. For instance, it has been observed that coating PLA nanoparticles with poloxamer 407, polox-amine 908, or poloxamer 338, as well as using PLA-PEG led to minimizing the secretion of inflammatory mediators such as AGP. On the other hand, the evaluation of potential novel toxicities of polymeric site-specific drug delivery systems includes the search for a depression or activation of the MPS when the system is administered intravascularly. For this route of administration, hemocompatibility also needs to be evaluated in terms of embolies due to particle aggregation or of hemolysis due to erythrocyte damages by the nanoparticles or their degradation products.

0 0

Post a comment