Abstract 1075: Chemically modified gamma PNAs targeting oncomiR-210 as a potential anticancer therapy
Authors: Anisha Gupta, Yanfeng Liu, Elias E. Quijano, W Mark Saltzman, Peter M. Glazer
Journal: Cancer Research (2016)

Abstract The specific aims of this study are to test the hypothesis that new generation PNA molecules targeting miR-210 delivered using nanoparticles will have therapeutic effects in xenograft mouse models and in human cancer cell lines. MicroRNAs (miRs) are a class of small non-coding RNAs (22-23nt) that regulate the translation and stability of mRNA during post-transcriptional events. miR profiling experiments reveal that certain miRs are widely over-expressed in several cancers, and inhibiting these miRs may offer a promising anticancer therapy. Little is known about how they work to cause cancer. This warrants further investigation to understand the relationship between miRNAs and cancer, but also to capitalize on fact that oncomiRs may be potent therapeutic targets. In particular, miR-210 exhibit differential expression levels in cancers, especially in hypoxic cancer cells, resulting in a demonstrated capability to affect cellular transformation and carcinogenesis by acting as an oncomiR. Many antisense molecules such as locked nucleic acids (LNA) have been developed that can target specific miRs, but they are few in number and often require further optimization for cellular delivery, off target toxicity, tumor selectivity and enzymatic resistance properties. Unlike most nucleic acids, PNA is a synthetic DNA/RNA mimic in which the phosphodiester backbone is substituted with a neutral N-(2-aminoethyl) glycine backbone. PNA has been shown to bind single-stranded targets sequence-specifically, with high binding affinity, and is not susceptible to protease or nuclease degradation. These salient features make PNAs excellent candidates for targeting miRs. Here, we used a new class of conformationally preorganized gamma peptide nucleic acids (γPNAs), which possess superior properties in terms of solubility, binding affinity, biocompatibility, and in vivo delivery in order to target miR-210. For cellular delivery, we used FDA approved poly(lactic-co-glycolic acid) (PLGA) nanoparticles. γPNA encapsulated in PLGA nanoparticles were evaluated in human cancer cell lines in vitro as well as in xenograft mouse model in vivo. Our results show that nanoparticles containing γPNAs targeting miR-210 cause significant delay in tumor growth in a xenograft mouse model. Further, histopathological analyses also support the enhanced antimiR-210 activity of γPNA. Hence our work will provides a) a framework for a antimiR-210 based therapeutics at the clinical level using γPNA; b) a promising clinically translatable system for selectively targeting cancer using a PLGA based nanoparticle system which can be scaled up easily; c) a step forward for personalized therapy for cancers by inhibiting specific miRs. In addition, use of hydrophilic chains (MP) at the γ position will improve the pharmacokinetic properties of PNA for preclinical and clinical studies for oncomiR-based therapeutics. Citation Format: Anisha Gupta, Yanfeng Liu, Elias E. Quijano, W Mark Saltzman, Peter M. Glazer. Chemically modified gamma PNAs targeting oncomiR-210 as a potential anticancer therapy. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1075.