Abstract

Exploiting an Antiviral Response to Improve Drug Delivery

Tom Anchordoquy, Professor, University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences

Early studies in gene delivery observed a period of time (days to weeks) after an initial injection when a repeat injection of lipoplexes had a minimal effect 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 shown that the refractory response involves the inhibition of particle uptake in addition to the silencing of gene 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 data suggest that this effect can be exploited to reduce off-target accumulation and improve delivery to the tumor during repeat injection.