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Design of nanodrugs for miRNA targeting in tumor cells (13-510-R) #MMPMID24749405
Yoo B; Ghosh SK; Kumar M; Moore A; Yigit MV; Medarova Z
J Biomed Nanotechnol 2014[Jun]; 10 (6): 1114-22 PMID24749405show ga
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 tonon-labile short linkers (GMBS; N-(?-Maleimidobutyryloxy)succinimide ester) or non-labile long linkers (PEG24; Succinimidyl-([N-maleimidopropionamido]-24 ethyleneglycol)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 ?v?3-specific cyclic RGDfK-PEG peptide does not confer an advantage in vitro at long incubation times required for inhibition.