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Abstract
The immunotoxicity of three generations of polyamidoamine (PAMAM) dendrimers (G-4,
G-5 and G-6) was evaluated in mouse macrophage cells in vitro. Using the Alamar blue
and MTT assays, a generation dependent cytotoxicity of the PAMAM dendrimers was found
whereby G-6 > G-5 > G-4. The toxic response of the PAMAM dendrimers correlated well
with the number of surface primary amino groups, with increasing number resulting
in an increase in toxic response. An assessment of intracellular ROS generation by
the PAMAM dendrimers was performed by measuring the increased fluorescence as a result
of intracellular oxidation of carboxy H2DCFDA to DCF both quantitatively using plate
reader and qualitatively by confocal laser scanning microscopy. The inflammatory mediators
macrophage inflammatory protein-2 (MIP-2), tumour necrosis factor-alpha (TNF-alpha)
and interleukin-6, (IL-6) were measured by the enzyme linked immunosorbant assay (ELISA)
following exposure of mouse macrophage cells to PAMAM dendrimers. A generation dependent
ROS and cytokine production was found, which correlated well with the cytotoxicological
response and therefore number of surface amino groups. A clear time sequence of increased
ROS generation (maximum at approximately 4 h), TNF-alpha and IL-6 secretion (maximum
at approximately 24 h), MIP-2 levels and cell death (approximately 72 h) was observed.
The intracellular ROS generation and cytokine production induced cytotoxicity point
towards the mechanistic pathway of cell death upon exposure to PAMAM dendrimers.
2010 Elsevier Inc. All rights reserved.