| Summary: | <p>Abstract</p> <p>Background</p> <p>The development of effective drug delivery systems capable of transporting small interfering RNA (siRNA) has been elusive. We have previously reported that colorectal cancer tumor xenograft growth was arrested following treatment with liposomal preparation of siDCAMKL-1. In this report, we have utilized Nanoparticle (NP) technology to deliver DCAMKL-1 specific siRNA to knockdown potential key cancer regulators. In this study, mRNA/miRNA were analyzed using real-time RT-PCR and protein by western blot/immunohistochemistry. siDCAMKL-1 was encapsulated in Poly(lactide-<it>co</it>-glycolide)-based NPs (NP-siDCAMKL-1); Tumor xenografts were generated in nude mice, treated with NP-siDCAMKL-1 and DAPT (γ-secretase inhibitor) alone and in combination. To measure <it>let-7a </it>and <it>miR-144 </it>expression <it>in vitro</it>, HCT116 cells were transfected with plasmids encoding the firefly luciferase gene with <it>let-7a </it>and <it>miR-144 </it>miRNA binding sites in the 3'UTR.</p> <p>Results</p> <p>Administration of NP-siDCAMKL-1 into HCT116 xenografts resulted in tumor growth arrest, downregulation of proto-oncogene c-Myc and Notch-1 via <it>let-7a </it>and <it>miR-144 </it>miRNA-dependent mechanisms, respectively. A corresponding reduction in <it>let-7a </it>and <it>miR-144 </it>specific luciferase activity was observed <it>in vitro</it>. Moreover, an upregulation of EMT inhibitor <it>miR-200a </it>and downregulation of the EMT-associated transcription factors ZEB1, ZEB2, Snail and Slug were observed <it>in vivo</it>. Lastly, DAPT-mediated inhibition of Notch-1 resulted in HCT116 tumor growth arrest and down regulation of Notch-1 via a <it>miR-144 </it>dependent mechanism.</p> <p>Conclusions</p> <p>These findings demonstrate that nanoparticle-based delivery of siRNAs directed at critical targets such as DCAMKL-1 may provide a novel approach to treat cancer through the regulation of endogenous miRNAs.</p>
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