Aptamer Therapeutics: The 21st Century`s Magic Bullet of Nanomedicine

Abstract

Aptamers, also known as chemical antibodies, are short single-stranded DNA, RNA or peptide molecules. These molecules can fold into complex three-dimensional structures and bind to target molecules with high affinity and specificity. The nucleic acid aptamers are selected from combinatorial libraries by an iterative in vitro selection procedure known as systematic evolution of ligands by exponential enrichment (SELEX). As a new class of therapeutics and drug targeting entities, bivalent and multivalent aptamer-based molecules are emerging as highly attractive alternatives to monoclonal antibodies as targeted therapeutics.Aptamers have several advantages, offering the possibility of overcoming limitations of antibodies: 1) they can be selected against toxic or non-immunogenic targets; 2) aptamers can be chemically modified by using modified nucleotides to enhance their stability in biological fluids or via incorporating reporter molecules, radioisotopes and functional groups for their detection and immobilization; 3) they have very low immunogenicity; 4) they display high stability at room temperature, in extreme pH, or solvent; 5) once selected, they can be chemically synthesized free from cell-culturederived contaminants, and they can be manufactured at any time, in large amounts, at relatively low cost and reproducibly; 6) they are smaller and thus can diffuse more rapidly into tissues and organs, leading to faster targeting in drug delivery; 7) they have lower molecular weight that can lead to faster body clearance, resulting in a low background noise for imaging and minimizing the radiation dose to the patient in diagnostic imaging. Thus, the high selectivity and sensitivity, ease of screening and production, chemical versatility as well as stability make aptamers a class of highly attractive agents for the development of novel therapeutics, targeted drug delivery vehicles and molecular imaging.In the review, we will discuss the latest technological advances in developing aptamers, its application as a novel class of drug on its own, as well as in surface functionalization of both polymer nanoparticles or nanoliposomes in the treatment of cancer, viral and autoimmune diseases.

Improving the Stability of Aptamers by Chemical Modification

“…The first-reported aptamers are naturally occurring RNA that bind small molecules and proteins to perform biological functions [3]. Later on the in vitro selection of nucleic acid aptamers from combinatorial libraries was invented [3,4]. This so-called SELEX ("systematic evolution of ligands by exponential enrichment") allows the progressive screening of highly specific ligands through iterative partitions and amplifications.…”

“…An RNA aptamer targeting the Most of these are aided by the medicinal chemistry approach, with the fast development of organic synthesis serving as a toolbox [10]. As a result of chemical modifications, many exceptional characteristics besides stability such as improved specificity [11], increased affinity [12][13][14][15], enhanced delivery and prolonged plasma residence [7,[16][17][18][19][20][21][22][23] have been reported and summarized [1,[3][4][5]10,24,25], among which aptamers conjugated by polyethylene glycol significantly promote aptamer's bio-distribution to varied tissues and organs in vivo and increase their plasma retention time, with prolonged half-lives for blood clearance [16,22]. Aptamers can be also encapsulated in or attached to biodegradable polymers/proteins for sustained drug delivery and prolonged release in vivo [18][19][20][21].…”

Selection of DNA Aptamers for Mycotoxins

“…RNA and DNA aptamers are not very stable in serum due to their susceptibility to degradation by nucleases; yet their degradation can be seen as an advantage. Since they are short lived in serum and are cleared rapidly by the kidneys, they are considered non-toxic 32 . In addition, oligonucleotides are not recognized as foreign objects to the immune system, therefore they are also considered non-immunogenic 20 .…”

“…Nucleases primarily attack pyrimidines, therefore protecting uracil and thymine is one option to lower nuclease susceptibility. Protection is carried out by replacing the 2' hydroxyl group with 2'-amino, 2'-fluoro, or 2'-O-methyl groups 32,34 .…”

“…One of the best known examples where an aptamer used as a drug is Pegaptanib sodium (Macugen). Approved in 2004 by the US Food and Drug Administration (FDA), Macugen is an RNA aptamer used to treat age-related macular degeneration, a condition which leads to loss of vision and which involves a specific isoform of vascular endothelial growth factor 32,35 . The aptamer was modified with 2'-O-methylated purines and 2'-fluorine-pyrimidines to protect against endonucleases, and also with polyethylene glycol (PEG) and a 3'-dT for protection against exonucleases and to improve its pharmacokinetic properties.…”