title: 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.
authors.forename: Byunghee
authors.initials: B
authors.lastname: Yoo
authors.forename: Subrata K
authors.initials: SK
authors.lastname: Ghosh
authors.forename: Mohanraja
authors.initials: M
authors.lastname: Kumar
authors.forename: Anna
authors.initials: A
authors.lastname: Moore
authors.forename: Mehmet V
authors.initials: MV
authors.lastname: Yigit
authors.forename: Zdravka
authors.initials: Z
authors.lastname: Medarova
mesh_terms: D045744:Cell Line, Tumor; D015195:Drug Design; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D035683:MicroRNAs / Q000008:administration & dosage* / Q000235:genetics*; D058990:Molecular Targeted Therapy / Q000379:methods*; D053769:Nanocapsules / Q000737:chemistry* / Q000648:ultrastructure*; D009374:Neoplasms, Experimental / Q000235:genetics* / Q000473:pathology*; D010316:Particle Size
chemical_list: D035683:MicroRNAs; D053769:Nanocapsules
references.citation: Nature. 2007 Oct 11;449(7163):682-8
references.pmid: 17898713
references.citation: Bioconjug Chem. 1993 Sep-Oct;4(5):347-52
references.pmid: 8274518
references.citation: Biomaterials. 2010 Nov;31(31):8032-42
references.pmid: 20673683
references.citation: Cancer Res. 2009 Oct 1;69(19):7495-8
references.pmid: 19773429
references.citation: Nat Rev Cancer. 2009 Apr;9(4):293-302
references.pmid: 19262572
references.citation: Cancer Res. 2010 Oct 1;70(19):7553-61
references.pmid: 20702603
references.citation: Bioconjug Chem. 2007 Sep-Oct;18(5):1391-6
references.pmid: 17630789
references.citation: J Virol. 2003 Jul;77(13):7174-81
references.pmid: 12805416
references.citation: Pharm Res. 2010 Sep;27(9):1788-99
references.pmid: 20424893
references.citation: EMBO Mol Med. 2012 Mar;4(3):143-59
references.pmid: 22351564
references.citation: ACS Nano. 2010 Oct 26;4(10):5887-96
references.pmid: 20863096
references.citation: Nat Med. 2007 Mar;13(3):372-7
references.pmid: 17322898
references.citation: Bioconjug Chem. 2005 Sep-Oct;16(5):1181-8
references.pmid: 16173796
references.citation: Cancer Res. 2006 Jul 1;66(13):6732-40
references.pmid: 16818648
references.citation: Proc Natl Acad Sci U S A. 2010 Jan 19;107(3):981-6
references.pmid: 20080556
references.citation: Nat Med. 2007 Jan;13(1):95-9
references.pmid: 17187073
references.citation: Cell. 2008 Jan 11;132(1):9-14
references.pmid: 18191211
references.citation: Proc Natl Acad Sci U S A. 2007 Sep 25;104(39):15549-54
references.pmid: 17875985
references.citation: Cell. 2004 Jan 23;116(2):281-97
references.pmid: 14744438
references.citation: Nat Cell Biol. 2009 Mar;11(3):228-34
references.pmid: 19255566
references.citation: J Am Chem Soc. 2010 Jun 23;132(24):8241-3
references.pmid: 20518524
references.citation: Int J Mol Med. 2010 Oct;26(4):533-9
references.pmid: 20818493
references.citation: Oncogene. 2013 Mar 21;32(12):1530-8
references.pmid: 22580603
references.citation: Cancer Res. 2011 May 15;71(10):3563-72
references.pmid: 21471404
references.citation: Nat Rev Genet. 2008 Feb;9(2):102-14
references.pmid: 18197166
references.citation: Nano Lett. 2009 May;9(5):1909-15
references.pmid: 19344179