Polyamidoamine dendrimer nanoparticle cytotoxicity, oxidative stress, caspase activation and inflammatory response: Experimental observation and numerical simulation

Mechanisms underlying the in vitro cytotoxicity of Polyamidoamine nano-dendrimers in human keratinocytes are explored. Previous studies demonstrated a systematic, dendrimer-generation-dependent cytotoxicity, oxidative stress, and genotoxicity. The emerging picture is of dendrimer endocytosis, endosomal rupture and subsequent mitochondrial attack and cell death. To understand the underlying mechanisms, the evolution of reactive oxygen species, intracellular glutathione, caspase activation, mitochondrial membrane potential decay, and inflammatory responses have been examined. Early-stage responses are associated with endosomal encapsulation, later-stage with mitochondrial attack. In all cases, the magnitude and evolution of responses depend on dendrimer generation and dose. The early-stage response is modelled using a rate equation approach, qualitatively reproducing the time, dose and generation dependences, using only two variable parameters. The dependence of the response on the nanoparticle physicochemical properties can thus be separated from internal cellular parameters, and responses can be quantified in terms of rate constants rather than commonly employed effective concentrations. From the Clinical Editor: This contribution reports on the intracellular mechanism of PAMAM dendrimer cytotoxicity in human keratinocytes. In all cases, the magnitude and evolution of responses depend on dendrimer generation and dose. Experimental data were supported by numerical simulation using only two variables. It is suggested that responses can be quantified in terms of rate constants rather than effective concentrations.