Nanoparticle-complexed antimiRs for inhibiting tumor growth and metastasis in prostate carcinoma and melanoma
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Journal of Nanobiotechnology Open Access
RESEARCH
Nanoparticle‑complexed antimiRs for inhibiting tumor growth and metastasis in prostate carcinoma and melanoma Manfred Kunz1†, Madeleine Brandl2†, Animesh Bhattacharya1,6†, Lars Nobereit‑Siegel1,2, Alexander Ewe2, Ulrike Weirauch2, Doreen Hering1, Anja Reinert3, Hermann Kalwa4, Juan Guzman5, Katrin Weigelt5, Sven Wach5, Helge Taubert5 and Achim Aigner2*
Abstract Background: MiRNAs act as negative regulators of gene expression through target mRNA degradation or inhibi‑ tion of its translation. In cancer, several miRNAs are upregulated and play crucial roles in tumorigenesis, making the inhibition of these oncomiRs an interesting therapeutic approach. This can be achieved by directly complementary single-stranded anti-miRNA oligonucleotides (antimiRs). A major bottleneck in antimiR therapy, however, is their efficient delivery. The nanoparticle formation with polyethylenimine (PEI) may be particularly promising, based on the PEI’s ability to electrostatically interact with oligonucleotides. This leads to their protection and supports delivery. In the present study, we explore for the first time PEI for antimiR formulation and delivery. We use the branched low molecular weight PEI F25-LMW for the complexation of different antimiRs, and analyse tumor- and metastasis-inhibi‑ tory effects of PEI/antimiR complexes in different tumor models. Results: In prostate carcinoma, transfection of antimiRs against miR-375 and miR-141 leads to tumor cell inhibition in 2D- and 3D-models. More importantly, an in vivo tumor therapy study in prostate carcinoma xenografts reveals anti-tumor effects of the PEI/antimiR complexes. In advanced melanoma and metastasis, we identify by a microRNA screen miR-150 as a particularly relevant oncomiR candidate, and validate this result in vitro and in vivo. Again, the sys‑ temic application of PEI/antimiR complexes inhibiting this miRNA, or the previously described antimiR-638, leads to profound tumor growth inhibition. These effects are associated with the upregulation of direct miRNA target genes. In a melanoma metastasis mouse model, anti-metastatic effects of PEI/antimiR treatment are observed as well. Conclusions: We thus describe PEI-based complexes as efficient platform for antimiR therapy, as determined in two different tumor entities using in vivo models of tumor growth or metastasis. Our study also highlights the therapeutic relevance of miR-375, miR-141, miR-150 and miR-638 as target miRNAs for antimiR-mediated inhibition. Keywords: Polyethylenimine, PEI, Antimir, PEI/antimiR nanoparticles, Therapeutic miRNA inhibition
*Correspondence: [email protected]‑leipzig.de † Manfred Kunz, Madeleine Brandl and Animesh Bhattacharya contributed equally to this work 2 Rudolf‑Boehm‑Institute for Pharmacology and Toxicology, Clinical Pharmacology, University of Leipzig, Haertelstrasse 16–18, 04107 Leipzig, Germany Full list of author information is available at the end of the article © The Author(s) 2020. This article is licensed under a Cr
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