Multifunctional Nucleic Acids for Tumor Cell Treatment

Abstract

We report on a multifunctional nucleic acid, termed AptamiR, composed of an aptamer domain and an antimiR domain. This composition mediates cell specific delivery of antimiR molecules for silencing of endogenous micro RNA. The introduced multifunctional molecule preserves cell targeting, anti-proliferative and antimiR function in one 37-nucleotide nucleic acid molecule. It inhibits cancer cell growth and induces gene expression that is pathologically damped by an oncomir. These findings will have a strong impact on future developments regarding aptamer- and antimiR-related applications for tumor targeting and treatment.

Selective delivery of therapeutic single strand antimiRs by aptamer-based conjugates

“…On the other hand, given the involvement of miRNAs in several fundamental cell processes, it is important to not perturb their levels in normal cells and thus to develop appropriate means for the selective delivery to cancer tissues. Whereas means of intracellular transport for double strand RNAi therapeutics, including miRNAs, are rapidly evolving [7,8], carriers for negatively charged antimiR sequences have been poorly addressed until now [9][10][11][12][13]. Therefore, here we pursued the development and validation of reliable non-toxic carriers able to selectively drive miRNA antagonist sequences to target tumor cells, to promote intracellular internalization and to functionally inhibit the corresponding oncogenic miRNA, without affecting non-tumor cells or tissues.…”

Targeting noncoding RNAs in disease

“…Additional delivery approaches include direct ORN conjugation using peptides such as pH low insertion peptide (pHLIP), which can deliver anti-miR-155 PNA to mice harboring B cell lymphomas in a pH-dependent manner (54,55). Use of tumor-specific aptamers, small nucleic acids whose 3D structure binds to specific cell surface proteins identified by systematic evolution of ligands by exponential enrichment (SELEX), is also used to improve targeting of PNAs (56,57). Importantly, many of these nanoparticle delivery methods are safe and biodegradable, indicating that they could rapidly be developed into "next-generation" miRNA therapeutics for clinical testing (Table 1 and Figure 3).…”

Optoribogenetic control of regulatory RNA molecules

“…1a) and analysed them in reporter gene assays that employ the expression of secreted Metrida luciferase or of enhanced green fluorescent protein (eGFP) with miR-21 target sites embedded in the 3'-UTRs of the respective mRNA (Supporting Fig. 1a,b,2) 31 . As controls, we constructed pre-miR-21 variants that bear a single point mutant (G11C) within the PAL aptamer that renders them binding-incompetent (SHC, SHD), a nonfunctional miR-21 domain (SHB, SHD) 32 , or with both domains altered (SHD, Fig.…”