PolyTran™ RNAi nanoplex (PT-NPX) carrying siRNAs against VEGF; VEGFR2; or EGFR achieves successful systemic delivery and significant anti-tumor activity in multiple xenograft tumor models

1498 The discovery of RNA interference (RNAi) using small interfering RNA (siRNA) molecules has generated significant attention for its potential application as a new therapeutic class. This potential is still unrealized due to lack of effective systemic delivery methods for siRNAs in vivo. In this study, we demonstrated the in vivo efficacy of systemic delivery of siRNA against human VEGF, mouse VEGFR2, and human EGFR using PolyTran™ Technology. PolyTran™ is a synthetic biodegradable cationic polypeptide which serves as a condenser for negatively charged siRNA and forms nanoparticle when mixed together with siRNA at appropriate charge ratios. PolyTran™ nanoparticles (PT-NPX) formed in different formulations are stable and can protect siRNA from nuclease-mediated degradation. We have shown that PT-NPX carrying VEGF-siRNA can be internalized by tumor cells and are capable of silencing VEGF expression in vitro. To test the in vivo efficacy and safety of this delivery method, nude mice bearing human epidermoid carcinoma A431 were treated intravenously (i.v.) with PT-NPX carrying siRNAs against either human VEGF; mouse VEGFR2; or human EGFR at 2mg/kg dose every other day for three weeks and compared with positive control using bevacizumab for VEGF and Erlotinib for EGFR. All cohorts treated with PT-NPX carrying active siRNAs demonstrated significant tumor growth inhibition similar to the positive control treated animals. In the same A431 xenograft model, the efficacy resulting from daily or every other day treatment regimen was superior to that of twice weekly or other regimens. Significant anti-tumor efficacy was also observed in human non-small cell lung cancer A549, and rhabdomyosarcoma A673 xenograft tumor models. No apparent toxicity or significant body weight loss were seen in the animals treated with PT-NPX suggesting that PolyTran siRNA NPX is safe in mice. Systemic tissue distribution was confirmed using fluorescent-labeled siRNA PT-NPX. These results provided the preclinical validation of PolyTran™ technology as an option for systemic delivery of potential therapeutic siRNAs for cancer treatment. We concluded that the PolyTran™ RNAi Nanoplex is an effective method of systemic delivery of siRNA and is a promising delivery system for the development of novel RNAi-based cancer therapeutics in humans.