Exploiting the Refractory Response to Limit Off-Target Accumulation

T. Anchordoquy
University of Colorado,
United States

Keywords: nanoparticle, drug delivery,


Early studies in gene delivery observed a period of time (days to weeks) after an initial injection when a repeat injection of lipoplexes had minimal effects on expression. This “refractory period” was originally attributed to viral promoters and CpG sequence that elicit the production of inflammatory cytokines which silence expression. However, subsequent studies with plasmids lacking these components still observed a refractory period. Ultimately, this effect is responsible for the inability to use repeat administration to achieve progressively greater levels of gene expression and obtain therapeutic efficacy. While relatively few studies have characterized delivery after repeat injection, our recent experiments have suggested that the refractory response is due to inhibition of particle uptake as opposed to silencing of expression. Although this results in reduced delivery to normal tissues that respond to cytokines, the immunosuppressed state of established tumors allows unimpeded delivery upon subsequent injections. Our preliminary data suggest that this effect can be exploited to improve delivery to the tumor and reduce off-target accumulation during repeat injection.