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Design of nanodrugs for miRNA targeting in tumor cells.

ABSTRACT: The delivery of oligonucleotide antagonists to cytosolic RNA targets such as microRNA represents an avenue for the post-transcriptional control of cellular phenotype. In tumor cells, oncogenic miRNAs, termed oncomirs, are tightly linked to processes that ultimately determine cancer initiation, progression, and response to therapy. Therefore, the capacity to redirect tumor cell fate towards therapeutically beneficial phenotypes holds promise in a future clinical scenario. Previously, we have designed "nanodrugs" for the specific inhibition of oncogenic microRNAs in tumor cells. The basic design of these nanodrugs includes dextran coated iron oxide nanoparticles, conjugated to a tumor-targeting peptide, and a locked nucleic acid (LNA)-modified antisense oligonucleotide that stably binds and inhibits the complementary mature miRNA. Here, we focus on elucidating an optimal nanodrug design for effective miRNA inhibition in tumor cells. Specifically, we investigate the choice of chemical linker for the conjugation of the oligonucleotide to the nanoparticles and evaluate the contribution of tumor-cell targeting to nanodrug uptake and functionality. We find that short labile linkers (SPDP; N-Succinimidyl 3-(2-pyridyldithio)-propionate) are superior to non-labile short linkers (GMBS; N-(gamma-Maleimidobutyryloxy)succinimide ester) or non-labile long linkers (PEG24; Succinimidyl-([N-maleimidopropionamido]-24ethyleneglycol)ester) in terms of their capacity to gain access to the cytosolic cellular compartment and to engage their cognate miRNA. Furthermore, using the nanodrug design that incorporates SPDP as a linker, we establish that the addition of tumor-cell targeting through functionalization of the nanodrug with the alphavbeta3-specific cyclic RGDfK-PEG peptide does not confer an advantage in vitro at long incubation times required for inhibition.

SUBMITTER: Yoo B

PROVIDER: S-EPMC4174340 | biostudies-literature | 2014 Jun

REPOSITORIES: biostudies-literature

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Design of nanodrugs for miRNA targeting in tumor cells.

Yoo Byunghee B Ghosh Subrata K SK Kumar Mohanraja M Moore Anna A Yigit Mehmet V MV Medarova Zdravka Z

Journal of biomedical nanotechnology 20140601 6

The delivery of oligonucleotide antagonists to cytosolic RNA targets such as microRNA represents an avenue for the post-transcriptional control of cellular phenotype. In tumor cells, oncogenic miRNAs, termed oncomirs, are tightly linked to processes that ultimately determine cancer initiation, progression, and response to therapy. Therefore, the capacity to redirect tumor cell fate towards therapeutically beneficial phenotypes holds promise in a future clinical scenario. Previously, we have desi ...[more]

PMID: 24749405

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Project description:IntroductionOsteosarcoma is the most common bone tumor and is characterized by the presence of malignant mesenchymal cells produced in the bone stroma. MiRNAs are known to function as post-transcriptional negative regulators of gene expression. Emerging evidence showed that miR-1225-5P functions as a tumor suppressor in several types of cancers. The detailed mechanisms of which miR-1225-5P suppresses tumor growth are not fully understood. The objective of the present study was to test the hypothesis that miR-1225-5P inhibits osteosarcoma cell growth in vitro and tumor growth in vivo by targeting YWHAZ expression.MethodsReal-time PCR and Western blot were carried out to test the expression of miR-1225-5P and YWHAZ in osteosarcoma cell lines. Luciferase assay was used to demonstrate whether miR-1225-5P targets YWHAZ 3' UTR. To assess the function of miR-1225-5P in human osteosarcoma cell lines, gain-of-function and loss-of-function of miR-1225-5P were performed by transfecting miR-1225-5P mimic or miR-1225-5P inhibitor into osteosarcoma cell lines. Furthermore, cell cycle analysis was performed to elucidate the possible mechanisms of the action of miR-1225-5P and YWHAZ in human osteosarcoma cells. The potential therapeutic effect of miR-1225-5p was tested in human osteosarcoma xenograft mouse model, by intravenous injection of miR-1225-5P into nude mice. Tumor sizes were measured and lung metastasis was counted after the mice were sacrificed.ResultsThe expression of miR-1225-5P was inversely correlated with the expression of YWHAZ in human osteosarcoma cell lines. Database search revealed that miR-1225-5P targeted YWHAZ 3' UTR. Transfection of miR-1225-5P mimic downregulated YWHAZ expression, which was demonstrated by real-time PCR, Western blot and luciferase assay. Over-expression of miR-1225-5P reduced human osteosarcoma cell growth, migration and invasion by downregulating YWHAZ expression. Cell growth, migration and invasion were increased by inhibiting miR-1225-5P in human osteosarcoma cells. The inhibition of cell growth, migration and invasion was rescued by over-expression of YWHAZ in osteosarcoma cells. Cell cycle analysis revealed that miR-1225-5P inhibited G1/G0 phase exit. In vivo xenograft model demonstrated that miR-1225-5P inhibited in vivo osteosarcoma tumor growth and lung metastasis.ConclusionOur findings suggested that miR-1225-5P inhibits osteosarcoma cell growth in vitro and tumor growth in vivo by targeting YWHAZ. This study suggested that miR-1225-5P can serve as a potential therapeutic method for treating osteosarcoma.

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Design of nanodrugs for miRNA targeting in tumor cells.

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Design of nanodrugs for miRNA targeting in tumor cells.

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