Therapeutic applications of AS1411 aptamer, an update review

Highlights

• Nucleolin is highly expressed both intracellularly and on the cell surface.

• It is considered as a potential target for the cancer diagnosis and therapy.

• AS1411 a 26-mer DNA aptamer that binds nucleolin.

• This review paper addressed recent progresses in nucleolin targeting by the AS1411.

Abstract

Nucleolin or C23, is one of the most abundant non-ribosomal phosphoproteins of nucleolus. However, in several cancers, nucleolin is highly expressed both intracellularly and on the cell surface. So, it is considered as a potential target for the diagnosis and cancer therapy.

Targeting nucleolin by compounds such as AS1411 aptamer can reduce tumor cell growth. In this regard, interest has increased in nucleolin as a molecular target for overcoming cancer therapy challenges. This review paper addressed recent progresses in nucleolin targeting by the G-rich AS1411 aptamer in the field of cancer therapy mainly over the past three years.

Introduction

Since first discovery in 1990, there has been enormous interest in the field of aptamers [[1], [2], [3], [4]]. Aptamers are short single-stranded DNA (ssDNA) or RNA molecules that thanks to their three-dimensional folding are able to bind a wide range of molecular targets with high affinity and specificity [5,6]. This property of aptamers has been exploited for developing targeted drug delivery system which can carry different types of cargoes into cells [[7], [8], [9]]. Aptamers are normally selected from a random library containing up to 10¹⁵ different sequences of 80 bases using a process called Systematic Evolution of Ligand by EXponential enrichment (SELEX). Each sequence of library is composed of a central random region flanked by two fixed sequences as primer binding platforms. SELEX is performed by treatment of the library with target of interest. Then, bound oligonucleotides are isolated from the unbound ones (partitioning) and amplified by polymerase chain reaction (PCR) in the case of DNA or reverse transcription PCR (RT-PCR) followed by transcription in the case of RNA. Each round of SELEX procedure includes one cycle of incubation, partitioning and amplification repeated several times to enrich the starting library (SELEX) [2,10,11]. Compared to antibodies, aptamers as molecular recognitions have several advantages including, smaller size, easier insertion of modifications, lower cost of production, lower immunogenicity, higher stability, equal or higher selectivity and affinity to target and lower batch to batch variations. These properties make them as suitable alternatives to antibodies. Moreover, Aptamers are not detected by immune system as foreign antigens [[12], [13], [14]]. Owing to these unique characteristics of aptamers, they have effectively been applied in medical procedures, including, tumor targeting, integration in nanoscale machinery, imaging, affinity purification, sensing in addition to diagnosis and therapy [13,15]. AS1411, a 26-mer DNA aptamer with G-quadruplex structure known as a non-SELEX aptamer that binds to nucleolin, was discovered serendipitously by Bates et al. [16]. This aptamer is heat stable and non-immunogenic. Also, it is resistant to DNase/RNase degradation in serum-containing medium [17]. The molecular target of AS1411 aptamer is nucleolin protein, which is found mainly in the nucleolus and distributed in the cytoplasm as well as on the cell surface. Nucleolin, one of the most abundant non-ribosomal phosphoproteins of nucleolus, was first discovered in 1973 in rat protein extract [18]. This multifunctional protein is involved in a wide range of cellular procedures like cell adhesion, cell division and migration, regulation of rRNA transcription, modification and processing of nascent pre-rRNA, regulation of telomerase maintenance as well as participates in DNA repair reactions and cell growth [19]. The expression and localization of nucleolin is often abnormal on rapidly proliferating cells, including various cancer cells and also is much higher in comparison to normal cells, which is related with an increase in the malignancy of cancers [20,21]. Nucleolin is needed for the initiation and activation of the TGF-β pathway, epidermal growth factor (EGF)-induced ERK signaling, the PI3K-AKT pathway, CXCR4 and CCR6 pathway signaling which could clearly affect the growth, viability, migration, colony formation ability and invasiveness of tumor cells [21]. Thus, nucleolin is considered as a remarkable and promising target that is targeted by the AS1411 aptamer for cancer therapy as well as targeted drug delivery [22]. In this review, we provide an update on reports about the application of AS1411 in cancer treatment with a particular focus on the past three years.