p. in jection of EGFR specific siRNA mediated by LPEI, we tested serum levels of pro inflammatory cytokines, in cluding IFN and TNF, which http://www.selleckchem.com/products/chir-99021-ct99021-hcl.html have been reported to be increased after siRNA delivered by lipids in vivo. Preparation and dose of the LPEI siRNA complexes were the same as in the above tumor growth inhibition experiment. As indicated in Figure 5A, after the last treat ment with 0. 6 nmol of LPEI complexed siRNAs, TNF production increases were induced in neither nude nor immunocompetent mice compared with the negative con trol group. On the other hand, LPS treatment led to a significant increase of serum TNF level in the positive control group, as expected. Similarly, at the end of the experiment no significant IFN increase was detected in LPEI siRNA complexes or glucose treated groups.

Discussion The success of siRNA based strategies in vivo relies on a delivery system which can efficiently protect and carry siRNA across various intracellular and extracelluar barriers into Inhibitors,Modulators,Libraries target cells in order Inhibitors,Modulators,Libraries to result in sequence specific mRNA degradation. In light of the poor clinical safety Inhibitors,Modulators,Libraries of viral vectors, linear polyethylenimine has emerged as a potent candidate because of its versatility and comparatively high gene transfection effi ciency. Because of its potential for DNA delivery, we used a commercial low molecular weight linear PEI. The Inhibitors,Modulators,Libraries in vitro data demonstrated that, upon delivery of LPEI, a significant EGFR protein down regulation was achieved in SPC A1 cells by transfection of an EGFR specific siRNA. Its efficiency was compar able to Lipofectamine 2000, a commonly used cationic liposome based transfection reagent.

As reported by many studies, this can be explained with the prop erty that cationic LPEI can potently compact negatively charged siRNAs into stable complexes with proper posi tive surface potential. This will facilitate their interaction Inhibitors,Modulators,Libraries with negatively charged cell surface components, and the resulting particle size of less than 100 nm is suitable for endocytosis. This also enhances the complexes delivery into cells, selleckbio eliciting specific RNAi effects. In one study, Urban et al. found that i. p. injection of LPEI complexed siRNAs targeting the c erbB2 neu recep tor resulted in a marked reduction of ovary tumor xeno graft growth. Grzelinski used LPEI complexed siRNA targeting secreted growth factor pleiotrophin to treat U87 glioblastoma subcutaneous xenograft bearing mice As a result, intact siRNA was successfully delivered and a 40% inhibition of tumor growth was observed over 3 weeks. Furtherly, in the orthotopic glioblastoma mouse model, a low dose of LPEI complexed PTN siRNA was injected into the central nervous system, also exerting an antitumor effect.