Nanoparticle-complexed antimiRs for inhibiting tumor growth and metastasis in prostate carcinoma and melanoma

Abstract

Background MiRNAs act as negative regulators of gene expression through target mRNA degradation or inhibition 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-inhibitory 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 systemic 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.

Integrated Analysis of Mutations, miRNA and mRNA Expression in Glioblastoma

“…In prostate carcinoma, transfection of antimiRs against miR-375 leads to tumor cell inhibition in 2D models, which further verifies its regulatory role in the carcinogenesis process. 37 AntimiRs transfection significantly reduced the expression of hsa-miR-135b-5p, resulting in regulation of the target APC genes. 38 An investigation of miR299 in papillary thyroid carcinoma (PTC) found it to be significantly dysregulated in PTC tissues compared to matched normal thyroid tissues.…”

MetastamiRs: The Role of MicroRNAs in the Metastatic Phenotype of Prostate Cancer

“…Proposed delivery methods include cationic-lipid transfection, polyethyleneimine or magnetic nanoparticles, atelocollagen, or viral vectors. (66,(134)(135)(136)(137)(138)(139)(140). While the majority of current research remains at the pre-clinical level, some miRNAs have reached early clinical development.…”

Mitochondrial Genetic and Epigenetic Regulations in Cancer: Therapeutic Potential

“…Nanoparticles carrying anti-miR-21 were able to selectively target triple-negative breast cancer (TNBC) cells to reduce miR-21 expression and activate apoptosis and proliferation control [ 295 , 296 ]. Inhibition of miR-150 and miR-638 was found to be efficient in reducing primary melanoma growth, as well as metastases [ 297 ]. Treatment with combined oxaliplatin and miR-204-5p on silica nanoparticles significantly decreased growth of colon cancer [ 298 ].…”