It has been established that cationic macromolecules in general destabilize the cell membrane, which can lead to lysis and cell death. The common conclusion present in current work echoes this observation: increasing dendrimer molecular weight and surface charge (both being generation-dependent) increases their cytotoxic behavior.
Initial studies on PAMAM toxicity showed that PAMAM was less toxic (in some cases, much less so) than related dendrimers, exhibiting minimal cytotoxicity across multiple toxicity screens, including tests of metabolic activity (MTT assay), cell breakdown (LDH assay), and nucleus morphology (DAPI staining). However, in other cell lines, the MTT assay and several other assays revealed some cytotoxicity. These disparate observations could be due to differences in sensitivity of the various cell lines used in each study to PAMAM; although cytotoxicity for PAMAM varies among cell lines, they remain less toxic than other dendrimer families overall.
More recently, a series of studies by Mukherjee et al. have shed some light on the mechanism of PAMAM cytotoxicity, providing evidence that the dendrimers break free of their encapsulating membrane (endosome) after being absorbed by the cell, causing harm to the cell's mitochondria and eventually leading to cell death. Further elucidation of the mechanism of PAMAM cytotoxicity would help resolve the dispute as to precisely how toxic the dendrimers are.
In relation to neuronal toxicity, fourth generation PAMAM has been shown to break down calcium transients, altering neurotransmitter vesicle dynamics and synaptic transmission. All of the above can be prevented by replacing the surface amines with folate or polyethylene glycol.
It has also been shown that PAMAM dendrimers cause rupturing of red blood cells, or hemolysis. Thus, if PAMAM dendrimers are to be considered in biological applications that involve dendrimers or dendrimer complexes traveling through the bloodstream, the concentration and generation number of unmodified PAMAM in the bloodstream should be taken into account.