Nucleic acid aptamers: clinical applications and promising new horizons

Abstract

Aptamers are a special class of nucleic acid molecules that are beginning to be investigated for clinical use. These small RNA/DNA molecules can form secondary and tertiary structures capable of specifically binding proteins or other cellular targets; they are essentially a chemical equivalent of antibodies. Aptamers have the advantage of being highly specific, relatively small in size, and non-immunogenic. Since the discovery of aptamers in the early 1990s, great efforts have been made to make them clinically relevant for diseases like cancer, HIV, and macular degeneration. In the last two decades, many aptamers have been clinically developed as inhibitors for targets such as vascular endothelial growth factor (VEGF) and thrombin. The first aptamer based therapeutic was FDA approved in 2004 for the treatment of age-related macular degeneration and several other aptamers are currently being evaluated in clinical trials. With advances in targeted-therapy, imaging, and nanotechnology, aptamers are readily considered as potential targeting ligands because of their chemical synthesis and ease of modification for conjugation. Preclinical studies using aptamer-siRNA chimeras and aptamer targeted nanoparticle therapeutics have been very successful in mouse models of cancer and HIV. In summary aptamers are in several stages of development, from pre-clinical studies to clinical trials and even as FDA approved therapeutics. In this review, we will discuss the current state of aptamers in clinical trials as well as some promising aptamers in pre-clinical development.

Figure 1

Generation of aptamers by SELEX. I) Aptamer pools are incubated with target for binding. II) Targets are thoroughly washed to remove non-binding species. III) Target-bound aptamers are eluted from the target. IV) Amplification of candidate aptamers by PCR (DNA) or RT-PCR and transcription (RNA). Steps I-IV is repeated for multiple rounds to deplete non-binders and enrich for target-binders. Following the final round of selection, binding nucleotides are cloned and sequenced to determine the specific nucleotide composition.

Figure 2

Use of aptamers to target cell surface ligands. A) Aptamers can be conjugated to various agents such as nanoparticles, imaging agents, or siRNAs in a site-specific manner. B) Aptamer-targeted therapeutics or imaging agents can be captured on the surface of cells or in specific tissues. C) Receptor-mediated internalization of aptamer conjugates can result in intracellular delivery and accumulation.