Interfering nanoparticles for silencing microRNAs.
ABSTRACT MicroRNAs (miRNAs) are single-stranded noncoding RNAs ∼21-nucleotide (nt) in length and regulate gene expression at the posttranscriptional level. miRNAs are involved in almost every area of biology, including developmental processes, disease pathogenesis, and host-pathogen interactions. Dysregulation of miRNAs in various disease states makes them potential targets for therapeutic intervention. Specific miRNAs can be silenced by anti-microRNAs (anti-miRs) that are chemically modified antisense oligonucleotides complementary to mature miRNA sequences. In vivo delivery of anti-miRs is the main barrier in achieving efficient silencing of target miRNAs. A new systemic delivery agent, interfering nanoparticles (iNOPs), was designed and prepared from lipid-functionalized poly-L-lysine dendrimer. iNOPs can efficiently deliver small RNAs, including short interfering RNAs, miRNA mimics, and anti-miRs. Systemic delivery of a chemically stabilized anti-miR-122 by iNOPs effectively silences miR-122 in mouse liver. Intravenous administration of 2 mg/kg anti-miR-122 complexed with iNOP-7 results in 83% specific silencing of target miRNA. The specific silencing of miR-122 by iNOP-7 is long lasting and does not induce an immune response.
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ABSTRACT: Introduction: Increasing evidence supports that microRNAs (miRNAs) play crucial roles in cancer through post-transcriptional gene silencing of their target genes, therefore, more and more effort has been devoted to develop miRNA-targeting therapeutics in cancer. MicroRNA-7 (miR-7) has been characterized as a potential tumor suppressor and regulates diverse fundamental biological processes of cancer cells including initiation, proliferation, migration, invasion, survival and death by targeting a number of oncogenic signaling pathways. Areas covered: This review examines evidence of the biological responses of miR-7 in cancer, with an emphasis on its regulation of the vital oncogenic signaling pathways. It also discusses the rationale, strategies and challenges of miR-7 as a potential therapeutic target for cancer. Expert opinion: With the increasing understanding of molecular mechanisms of miR-7-mediated regulatory networks and the advancement of miRNA-based therapeutics, targeting miR-7 may be a potential and promising strategy for cancer therapy.Expert Opinion on Therapeutic Targets 03/2015; 19(3):415-426. DOI:10.1517/14728222.2014.988708 · 4.90 Impact Factor
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ABSTRACT: Aberrantly expressed microRNAs (miRNAs) are involved in breast tumorigenesis. It is still unclear if and how miRNAs-221/222 are implicated in breast cancer and the resistance to estrogen receptor modulator tamoxifen. We investigated the roles and mechanisms of miR-221/222 in breast cancer cells, particularly in modulating response to tamoxifen therapy. MCF-7 and MDA-MB-231 breast cancer cells were transfected with antisense oligonucleotides AS-miR-221 and AS-miR-222 and their expression of miR-221 and miR-222 was assessed. The correlation of miR-221/222 with tissue inhibitor of metalloproteinase-3 (TIMP3) expression was investigated by fluorescence quantitative PCR and western blotting analysis. The therapeutic sensitivity of these cells, transfected and untransfected, to tamoxifen was determined. Transfection of AS-miR-221 and AS-miR-222 dramatically inhibited expression of miR-221 and miR-222, respectively, in both MCF-7 and MDA-MB-231 cells (P<0.05-0.01). Downregulation of miR-221/222 significantly increased the expression of TIMP3 compared with controls (P<0.05-0.01). The viability of estrogen receptor (ER)-positive MCF-7 cells transfected with AS-miR-221 or/and AS-miR-222 was significantly reduced by tamoxifen (P<0.05-0.01). We have demonstrated for the first time that suppression of miRNA-221/222 increases the sensitivity of ER-positive MCF-7 breast cancer cells to tamoxifen. This effect is mediated through upregulation of TIMP3. These findings suggest that upregulation of TIMP3 via inhibition of miRNA-221/222 could be a promising therapeutic approach for breast cancer.Cancer Gene Therapy advance online publication, 13 June 2014; doi:10.1038/cgt.2014.29.Cancer Gene Therapy 06/2014; DOI:10.1038/cgt.2014.29 · 2.55 Impact Factor
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ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is a severe pancreatic malignancy and is predicted to victimize 1.5% of men and women during their lifetime (Cancer statistics: SEER stat fact sheet, National Cancer Institute, 2014). miRNAs have emerged as a promising prognostic, diagnostic and therapeutic tool to fight against pancreatic cancer. miRNAs could modulate gene expression by imperfect base-pairing with target mRNA and hence provide means to fine-tune multiple genes simultaneously and alter various signaling pathways associated with the disease. This exceptional miRNA feature has provided a paradigm shift from the conventional one drug one target concept to one drug multiple target theory. However, in vivo miRNA delivery is not fully realized due to challenges posed by this special class of therapeutic molecules, which involves thorough understanding of the biogenesis and physicochemical properties of miRNA and delivery carriers along with the pathophysiology of the PDAC. This review highlights the delivery strategies of miRNA modulators (mimic/inhibitor) in cancer with special emphasis on PDAC since successful delivery of miRNA in vivo constitutes the major challenge in clinical translation of this promising class of therapeutics.Advanced Drug Delivery Reviews 09/2014; DOI:10.1016/j.addr.2014.09.006 · 12.71 Impact Factor