There was no statistical difference between the LPEI complexed non EGFR specific siRNA and glucose Src Bosutinib treated groups, demonstrating the specificity of target mRNA degradation in mechanism, and no antitumor effect from the non viral vector was observed.Moreover, there are some studies, which reported high dose of naked siRNA delivery in mice by high pressure tail injections. However, this method was considered to be too toxic and not compatible with clin ical application. In comparison, LPEI can carry a lower dose of siRNA to effectively exert an antitumor effect in vivo. One key factor for successful RNAi based therapy Inhibitors,Modulators,Libraries is to choose the right target genes. With increasing knowledge of cancer cell signaling pathways, inhibition Inhibitors,Modulators,Libraries of critical sig nal transducers involved in proliferation or survival is a promising direction for developing siRNA based cancer therapeutics.

EGFR is a glycoprotein with a molecular weight of 170,000 to 180,000, and an intrinsic tyrosine specific protein Inhibitors,Modulators,Libraries kinase, stimulated upon epidermal growth factor binding. A previous study indicated that significant and specific down regulation of EGFR expres sion by vector based short hairpin RNA can in hibit human lung adenocarcinoma Inhibitors,Modulators,Libraries cell growth, induce cell apoptosis, and subsequently in crease sensitivity to cisplatin, doxorubicin, and paclitaxel by about 4 to 7 fold in these two HLAC cell lines, re spectively. Based on these results, the present study has taken a giant step forward by successfully in vivo applying the EGFR target siRNA complexed with LPEI, eliciting a marked antitumor effect through specific EGFR down regulation.

Given that it is crucial to identify potential side effects induced by this siRNA based therapeutic system, Inhibitors,Modulators,Libraries toxicity and production of pro inflammatory cytokines after siRNA based therapy were examined. As shown in the repeated injection experiment, no adverse effect on hep atic or renal function was observed from LPEI complexed siRNA EGFR treatment. Microscopic examinations of the heart, liver, kidneys and lungs also revealed no detectable damage. As for immunogenicity, treatment with EGFR specific or non specific siRNA complexed with LPEI did not change serum TNF or IFN levels compared with glucose treated mice, which as an indication of a severe immune response, can be triggered by siRNA over dosage, an improper sequence design, or certain delivery vectors and induce injuries in vitro or in vivo.

Similarly, Grzenlinski found no obvious production of pro inflammatory cytokines in a glioblastoma mouse model, while Bonnet sellckchem et al. revealed no induction of inflammation or liver damage was observed after i. v. injection of the formulation. Accordingly, the LPEI siRNA based therapy seems safe for clinical application. As a new technology, siRNA based therapy has rapidly moved into the clinic.