Populations of CD68 and TLR4 expressing cells were not significantly changed, compared to the groups treated with siGFP -LPs or PBS, indicating the absence of innate immune stimulation by the siRNA and/or the LPs. selleck compound Conclusion: C12-200 LPs loaded with siRNA to procollagen I and likely other fibro-genic transcripts are a promising approach to inhibit liver fibrosis progression and promote

its regression in vivo. Disclosures: Alfica Sehgal – Employment: Alnylam Pharmaceuticals Detlef Schuppan – Consulting: Boehringer Ingelheim, Aegerion, Gilead, Gen-zyme, GSK, Pfizer, Takeda, Sanofi Aventis, Silence The following people have nothing to disclose: Carolina Jimenez Calvente, Yong Ook Kim Introduction: Liver fibrosis results Selleck Ulixertinib from the excessive accumulation

of extracellular matrix including collagens. The development of effective antifibrotic agents is in hampered by a lack of highly specific and liver targeted drugs. Small interfering RNA (siRNA) is a powerful tool for post-transcriptional gene silencing. The systemic delivery of naked siRNAs is fraught with obstacles, such as degradation by serum and tissue nucleases, inefficient endocytosis by tissue cells and rapid excretion via the kidneys. Lipid-like particles (LPs) could permit efficient delivery of siRNA, minimizing interference with blood cells and plasma, thus having low or no side effects. We could show that C12-200 LPs when loaded with siRNA to procollagen α1 (I) induce a 50-80% target knockdown in liver fibrosis models in vivo. However, distribution and cell-specific uptake of these LPs remained unkown. Methods: 3 mg of C12-200 LPs were linked to 50 μg of DiR near infrared (NIR) or DiI lipid dyes. One hour later, the unbound dye molecules were removed by centrifuga-tion. Lipid dye binding and the final composition of the liposo-mal dispersion was confirmed by light scattering flow cytometry and fluorescent microscopy. Immediately after labeling, Mdr2 deficient

and CCL4-fibrotic mice, and Thymidine kinase their wildtype or untreated littermates, were subjected to a single i.v. injection of DiR- or DiI-labeled C12-200 LPs. Their in vivo distribution was determined by NIR-in vivo imaging and their co-localization with liver cell subsets was determined by fluorescent IHC at 30 min, 4, 24, and 48 h post-injection. Results: 30 min after injection, 90% of administered DiR-labeled C1 2-200 LPs were found in the liver of Mdr2KO and CCL4-treated mice and their nonfi-brotic controls. Maximum hepatic accumulation was found at 24 h. DiI-labeled C12-200 LPs localized differently in the two fibrosis models. At 24 h in Mdr2KO mice, 11%, 35%, 15%, 65% and 5% of hepatocytes (Albumin+), mesenchymal cells (vimentin+), activated HSCs (α-SMA+), Kupffer (CD68+) and endothelial cells (CD31+), respectively, took up DiI-labeled C12-200 LPs, whereas in their wildtype controls or CCL4-untreated littermates these percentages were much lower (5%, 1.