(645a) Targeted, Endosomolytic Polymer Delivery Vehicles for siRNA

Small interfering RNA (siRNA) has been used to silence many genes in a variety of cell types and is of great interest as a cancer therapeutic. Similar to other macromolecular drugs, siRNA is predominantly trafficked to the lysosome and degraded enzymatically. In addition, serum proteases are capable of rapid siRNA degradation. Therefore, an optimal therapeutic siRNA delivery approach would combine serum-stability, long circulation times, and tissue-specific targeting, with efficient endosomal uptake and escape prior to lysosomal trafficking. Previously, we developed a carrier that addressed serum-stability and endosomal uptake and escape. This carrier, polymerized via reversible-addition fragmentation chain transfer (RAFT) polymerization, combines positively-charged dimethylaminoethyl methacrylate (DMAEMA) as a siRNA-condensing block with a pH-responsive block to enable endosomal escape. To further develop our therapeutic approach, we have introduced specific targeting moieties by taking advantage of the telechelic nature of RAFT polymerizations, enabling folate receptor-mediated endocytosis by introducing folate moieties. In vivo evaluation of this carrier is currently underway and data will be presented highlighting biodistribution and efficacy in cancer xenograft-bearing animal models.