Review Article

Aptamer: "smart bomb" facilitates delivery of drugs to the cancer cells Nirav Patel*, Neha Vadgama Dept. of Pharmaceutical Sciences, Saurashtra University, Rajkot 360 005, Gujarat, India


*For correspondence

Dr. Nirav V. Patel,

Dept. of Pharmaceutical Sciences,

Saurashtra University, Rajkot 360 005,

Gujarat, India.


Received: 18 September 2015

Accepted: 27 September 2015


Aptamers are single-stranded synthetic DNA- or RNA-based oligonucleotides that fold into various shapes to bind to a specific target. They may serve as both drugs and drug-carriers. They bind to various targets like lipids, nucleic acids, proteins, small organic compounds, and even entire organisms. Aptamers may also serve as drug-carriers or nanoparticles helping drugs to get released in specific target regions. Due to better target specific physical binding properties aptamers cause less off-target toxicity effects. They are obtained using iterative method, called (Systematic Evolution of Ligands by Exponential Enrichment) SELEX and cell-based SELEX (cell-SELEX). They have been used in biosensing, drug delivery, disease diagnosis and therapy (especially for cancer treatment). In this review, we have summarized aptamers, its types, limitations, advantages, in clinical studies and recent applications of DNA and RNA aptamers in cancer theranostics. Furthermore, with the development of nanoscience and nanotechnology, the conjugation of aptamers with functional nanomaterials paved an exciting way for the fabrication of theranostic agents for cancers, which might be a powerful tool for cancer treatment. Due to their excellent specificity and high affinity to targets, aptamers have attracted great attention in various fields in which selective recognition units are required.

Keywords: Aptamer, Tumor targeting, Nanoparticle-aptamer conjugate, Case studies, Clinical studies


Nucleic acids are biopolymers, or large biomolecules, essential for all known forms of living organisms, which are considered to be the foundation of life. Nucleic acids, which include DNA (deoxyribonucleic acid) and RNA (ribonucleic acid), are made from monomers known as nucleotides are of great importance due to their functions in encoding, transmitting, and expressing genetic information. Recent findings disclose that specific sequences of nucleic acids, referred as aptamers, possess unique binding characteristics to their targets and the term aptamer is derived from the Latin root 'aptus', which means 'to fit,' a reflection of the high specificity with which aptamers bind their targets.1,2 Aptamers are single-stranded DNA or RNA (ssDNA or ssRNA) molecules that can bind to pre-selected targets including proteins and peptides with high affinity and specificity. Aptamers are typically 20–100 nucleotides in length, and their unique structure is determined by this nucleotide sequence. These molecules can assume a variety of shapes due to their tendency to form helices and single-stranded loops, explaining their adaptability in binding to various targets. They are used as sensors, and therapeutic tools, and to regulate cellular processes, as well as to guide drugs to their specific cellular targets. Contrary to the actual hereditary material, their specificity and characteristics are directly determined by their tertiary structure instead of their primary sequence. Since their findings, aptamers have acquired marvelous attention for the design of biosensors, target imaging agents and drug delivery. Theoretically, they can be selected for any given target.3-5 To date, abundant high-affinity aptamers have been selected for a broad range of target molecules like small molecules, metal ions, drugs, toxins, peptides, proteins, viruses, bacteria, and even whole cells.6-11

For the treatment of oncologic disease like cancers, it is required that an anticancer drug is directly delivered to the tumor tissues for an extended period of time without killing the surrounding noncancerous tissue and this can be possible due to advances in nanotechnology because they have two desirable properties like targeted delivery and controlled drug release. Cancer-specific drug delivery may be achieved by both local and systemic administration of specially designed vehicles. These vehicles may be engineered in such a way that they can encapsulate the cytotoxic drug for tailored made release and targeting those vehicles to the tumor cells with ligands which recognize tumor-related antigens 12, 13. Several unique properties of aptamers make them smart tools for use in a wide array of applications for targeted cancer therapy. Aptamers bind to targets with high affinity, demonstrating typical dissociation constants in the pico- to nano-molar range, comparable to monoclonal antibodies.14,15

Aptamers recognize virtually an unlimited spectrum of molecular targets, unbound by limitations of immunogenicity. Because aptamers are generated chemically, precise control can be exercised over their synthesis, purity and pharmokinetic profile. These combined properties enable aptamers to be rightfully named as cutting edge therapeutic tools to treat disease into the 21st century. However, several exclusive distinctiveness of aptamers promise their extraordinary advantages compared to antibodies like they can be selected in vitro for any toxic or non-immunogenic targets, synthesized with high reproducibility and purity with a large quantity, easier to further modify them with functional groups, very stable and can recover their active conformation after thermal denaturation etc.16,17 The most exciting applications of aptamers is in developing nanotechnology approach for the development of new biomedical devices for analytical, imaging, drug delivery and many other medical applications. Nanoparticle-aptamers conjugate may be used for drug delivery and bioimaging in cancer diagnostics and enhance the specific binding of the nanoparticles via the specific aptamer binding to the target molecule.18 They may be used to improve the measurement of cancer-relevant parameters and, so, contribute to the development of intelligent medical devices. An aptamer-based therapeutic (known as pegaptanib or Macugen, marketed by Pfizer) has already received US FDA approval for the treatment of age-related macular degeneration (AMD).19 A potential therapeutic, AS141120,21 for acute myeloid leukaemia, and NOXA1222,23 for multiple myelomaand non-Hodgkin's lymphoma, aptamers developed by Antisoma and NOXXON, respectively, are in clinical trials.24,25 Those Aptamers who gave positive results against various cancer cell lines, they can be used initially for biomarker discovery and later for diagnostic and therapeutic purposes. Targeted therapeutic drug delivery to cancer cells and tissues possesses a bright future with the help of aptamers, which can reduce side effects of most chemotherapeutic drugs. In this review, we have introduced aptamers technology and their development and functionalities related to nanoparticle modification.

Aptamer affinity, structure and examples

Aptamers are a class of high-affinity molecules derived from single stranded DNA, RNA or unnatural oligonucleotides that have been selected in vitro from a pool of (1014 – 1015) of the – the random oligonucleotides for their high affinity binding to their cognate targets. Aptamers may be circularized, linked together in pairs or clustered onto a substrate.26,27 Complex interactive forces of aptamers are responsible for the selective binding affinity towards targets. Aptamers fold through intramolecular interaction to create tertiary conformations with specific binding pockets that bind to their target molecules with high specificity and affinity. This tertiary conformation is analogous to the globular shape of tRNA. Aptamers are generated using a process termed systematic evolution of ligands by exponential enrichment (SELEX; Figure 1) which was first described in 1990.28,29

Figure 1: Systematic evolution of ligands by exponential enrichment (SELEX).

The pharmacokinetic properties of aptamers must be improved prior to in vivo applications because these molecules are susceptible to nuclease degradation or renal clearance in vivo. They are highly stable and may tolerate a wide range of temperature, pH (~4 – 9) and organic solvents without loss of activity. Therefore, their pharmacokinetic properties must be enhanced prior to in vivo applications. Their properties can be optimized by 1) capping their terminal ends, 2) substituting naturally occurring nucleotides with unnatural nucleotides that are poor substrates for nuclease degradation (i.e. 2'-, 2'-OCH3 or 2'-NH2 modified nucleotides), 3) substituting naturally occurring nucleotides with hydrocarbon linkers, and 4) use of L-enantiomers of nucleotides to generate mirror image aptamers commonly referred to as spiegelmers.30–32 Aptamers can also be stabilized using locked nucleic acid modifications to reduce conformational flexibility.33 Aptamers size may be increased by conjugation with polymers such as polyethylene glycol (PEG), which can prolong the rate of clearance of aptamers.34 The aptamer must be directed towards receptors that are preferentially or exclusively expressed on the plasma membrane of cancer cells in tumors or directly delivered to extracellular matrix molecules that are expressed preferentially in tumors. A large number of aptamers have been isolated that bind specifically to receptors on cancer cells and rose against cancer-associated antigens (Table 1).35–37

The overview of systematic evolution of ligands by exponential enrichment (SELEX): the aptamer-selection strategy38-41

Aptamer sequences that have defined and unique properties are identified from a large pool comprising a randomized combinatorial library through an iterative process of nucleic acid selection and amplification called Systematic Evolution of Ligands by Exponential Enrichment (SELEX). The SELEX approach is commonly used to select interesting aptamers by an iterative process of in vitro selection and amplification. The SELEX process starts with a chemically synthesized random oligonucleotides library, which contains 1013 to 1016 motifs of different sequences. For the selection of RNA aptamers, the DNA library is converted into an RNA library before the RNA SELEX process. The selection process consists of five steps: 1) binding, incubation of the library with the target; 2) partition, isolation of target-bound sequences from unbound ones; 3) elution from a complex via chromatography; 4) amplification, generation of a new pool of nucleic acids by PCR (for DNA libraries) or RT-PCR (for RNA libraries); and 5) conditioning, in which in vitro transcription and purification of relevant ssDNA are included. Isolation of the bound DNA/RNA from unbound ones is the most crucial step.

Generally, 8-15 rounds of selection and efficient removal of unbound species are preferred to obtain an ideal aptamer with sufficient specificity and binding affinity. The traditional SELEX process is often labor-intensive, time-consuming, and cost of finances and resources. Therefore, most of the works were focused on shortening the selection period, while maintaining the aptamer affinity to targets.

To overcome these limitations, cell-SELEX was developed and has become one of the most widely- used methods for aptamer selection. Unlike traditional SELEX targeting on isolated molecules, cell-SELEX targets a whole live cell. It ensures the native conformations of the cell-surface proteins, and the developed aptamers are highly suitable for biological applications. Moreover, there is no need to know the quantity or types of proteins on the cell surface, which brings great convenience and simplifies the selection process. The selected aptamers by cell-SELEX can specifically target one specific type of cancer cells but not the others or normal cells, indicating their high selectivity. The main steps of cell-SELEX are similar to traditional SELEX, including incubation, partitioning, and amplification. More details are illustrated in Figure 2. Cell-SELEX has a set of unique properties, such as the ability of simultaneous generation of a panel of aptamers (which may have different molecular targets) and no requirement of prior knowledge of a cell's molecular signature. The improvements in the selection process have generated a large number of aptamers against various targets with high affinity, leading to their broader applications not only limited in (bio) analytical fields, but also in disease treatment, especially in cancer therapy. Some aptamers have been developed against a few types of cancer cells, including leukemia (e.g., lymphocytic leukemia, myeloid leukemia), liver cancer, lung cancer, and brain cancer.

Figure 2: Cell-SELEX to identify aptamers that targets membrane proteins. First, a DNA library is transcribed and incubated with normal cells. Second, unbound nucleic acids are exposed to target cells that overexpress the membrane protein of interest for selection. Third, bound nucleic acids are recovered and amplified by PCR and subjected to further rounds of selection. This SELEX cycle is repeated 15 - 20 times to enrich for sequences that bind to the target cells. SELEX has undergone several generations of refinements and modifications over the years. More automated selection processes are possible and they may be selected as either DNA or RNA and under conditions that match the environment of the intended application more closely.

Aptamer's functioning

There are three types of aptamers: DNA, RNA, and peptide aptamers. All have very similar properties but are definitely exclusive. It is theoretically possible for aptamers to be used against any molecular target. Because they structurally conform to bind to their targets, this gives aptamers a wider range of possible targets when compared with antibodies, which require antigens and epitopes along with an immune response for their targets.

DNA & RNA aptamers

Deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) aptamers are the most common type of aptamers. They are chosen from a pool of random nucleic acid sequences and put through several cycles for optimization in a process called SELEX. These aptamers are single stranded and typically around 15-60 nucleotide bases in length - the longest sequences have been selected at 220 nucleotides. Upon recognition of their target, aptamers bond by complementary RNA base pairing. This base pairing creates secondary structures such as short helical arms and single stranded loops. Combination of these secondary structures results in the formation of tertiary structures that allow aptamers to bind to targets via van der Waals forces, hydrogen bonding and electrostatic interaction – aligning with the ways antibodies bind to antigens. When this tertiary structure forms, the entire aptamer folds into a stable complex with the target ligand. These are called aptamer-target complexes. This three-dimensional structure allows aptamers to function like antibodies. Aptamer to protein binding ability is in the range of monoclonal antibodies. DNA and RNA aptamers are functionally similar but have several differences. DNA aptamers are inherently more stable, cheaper, and easier to produce. RNA also requires reverse transcription, in which RNA must be converted base-for-base into DNA - whereas DNA does not require this extra stage in the SELEX process. DNA and RNA aptamers can also differ in sequence and folding pattern even when selected for the same target.

Peptide aptamers

Peptide aptamers are small, simple peptides with a single variable loop region tied to a protein on both ends. Peptide aptamers only bind to their targets with this variable loop region. This contrasts to DNA and RNA aptamers which bind using their entire sequence. Being tied to this loop region reduces the flexibility of peptide aptamers, and thus effectiveness. Peptide aptamers display high specificity properties. The newest form of aptamers, much is still unknown about these structures. They have found use in the inhibition of a target's ability to interact with proteins.

Limitations in aptamer applications

  1. Aptamer degradation
  2. Aptamer excretion from the bloodstream by renal filtration
  3. Control of the duration of action
  4. Interaction of aptamers with intracellular targets
  5. Generation of aptamers using unpurified target proteins
  6. Aptamer cross-reactivity
  7. Automation of aptamer generation

Aptamers as therapeutic Drugs

Most of the drugs target cell's various compartments where cell based diseases originate. The most critical role in cell function is played by cell signaling which controls the activation of cell's normal growth, raising cellular disorders, spreading diseases, and so forth. The cellular compartments and underlying mechanisms are therefore natural targets for drugs. Due to the specific recognition ability of aptamers with their target biomolecules, they can be used to modulate some biological activities. Therefore, aptamers are able to work as therapeutic agents for several diseases by interfering with key molecules in the process of the disease development.42,43

For example, the first aptamer (named Macugen) targeted to human VEGF for the treatment of age-related macular degeneration (AMD) was approved by U.S. FDA in 2004. Macugen has just got approved in ophthalmology as antiangiogenesis drug. This is first ever aptamer based drug. This is tried in the treatment of age-related macular degeneration.44,45. Macugen is also the first aptamer treatment approved by the FDA. Macugen inhibits the binding of 125I-VEGF to VEGF receptors Flt- 1 and KDR expressed on porcine aortic endothelial cells (source: SomaLogic Inc.). Macugen, a compound which was earlier (in 1998) taken by NeXstar with a name NX 1838, finally was pushed for early clinical development. In the SELEX based NeXtar discovery the first step was to place a pool of individual nucleotides in a test tube with the appropriate RNA or DNA polymerase to make aptamers that were poured over a column of VEGF to determine which ones would bind with fairly high affinity. Using the traditional SELEX technique those binders were then amplified, and more were made to find the ones with the highest affinity. Several cycles were repeated until the best binders were discovered. Thus finally the Macugen aptamer was discovered. Eye tech then tested the aptamer in its models to ensure that it behaved in the expected way, that is, to stunt vessel growth. It also performed standard toxicology and pharmacology tests. This is how Macugen has appeared as first successful aptamer based drug.

Recently, aptamers used for cancer treatment were also developed as therapeutic agents. The most successful aptamer for cancer treatment probably is AS 1411. AS 1411 was developed by Aptamera (Louiseville, KY), formally named as AGRO100. It is an unmodified guanosine rich 26-mer DNA strand.46 AS1411, which was discovered via serendipity instead of SELEX process, showed growth-inhibitory properties in several cancer cell lines, including prostate, breast, lung and cervical cancer cell lines. The exact mechanism for the therapeutic activity of AS1411 was not totally understood. However, there were several pathways that might be induced by AS1411 for its growth-inhibitory activity. AS1411, known as guanosine rich oligonucleotides, could form a stable G-quartet-containing structure, which was able to bind with nucleolin. Nucleoline was highly expressed on the surface and cytoplasm of cancer cells. Therefore, AS1411 was able to specifically bind to the surface of cancer cells and then internalize into the cells.47 Further studies showed that the internalized aptamer-nucleolin complex resulted in the inhibition of DNA replication and cytotoxicity against cancer cells. AS1411 could also bind with nuclear factor-κB to inhibit its activity and destabilize BCL-2 mRNA that all can inhibit cell proliferation 48. This aptamer has been undergone the animal trials and is in Phase II clinical trials for AML. Interestingly, Choi et al. found that the cancer-selective antiproliferative activity of aptamers might be due to the G-rich oligodeoxygnucleotides, which formed the G-quadruplex structure. This G-quadruplex structure enhanced the nuclease digestion resistance and cell uptake efficiency. Meanwhile, it bound to several important proteins to interfere with intracellular pathways and resulted in the antiproliferative activity for cancer cells. These findings might shed light on the design and development of G-rich aptamers for cancer treatments.

Recently, a study on aptamer-based tumor-targeted drug delivery for photodynamic therapy has been performed by Shieh et al.49 Here a specialized G-rich DNA structure, G-quadruplex, was studied for its special physical characteristics and biological effects. This reference has reported a novel strategy of using G-quadruplex as a drug carrier to target cancer cells for photodynamic therapy (PDT). A G-quadruplex forming AS1411 aptamer was reported to have properties which could help to be physically conjugated with six molecules of porphyrin derivative, 5, 10, 15, 20-tetrakis (1-methylpyridinium-4-yl) porphyrin (TMPyP4), to fabricate the aptamer-TMP complex. The TMPyP4 molecules in the complex had been identified to bind tightly to the aptamer by intercalation and outside binding. The effect of the G-quadruplex structure as a carrier for the delivery of TMPyP4 into cancer cells by nucleolin-mediated internalization was investigated. The results showed that the aptamer-TMP complex exhibited a higher TMPyP4 accumulation in MCF7 breast cancer cells than in M10 normal epithelium cells. After being treated with light for 180s, the photodamage in MCF7 cells was larger than in M10 cells. These results indicated that the TMPyP4 delivery and uptake were mediated by the specific interaction of the aptamer-TMP complex with nucleolin on the cellular surface and that the use of the AS1411 aptamer as a drug carrier may be a potential tactic in cancer therapy. Thus the aptamer AS1411 which has been previously addressed as an anticancer agent is found to have capacity to also be used as a drug carrier for specific purposes. Table 2 Shows Aptamer-Directed Active Targeting Polymeric Nanoparticles for Cancer Treatment.

Aptamers in the clinic 50, 51

There are now several aptamers that have undergone clinical trials (Table 3), and a consideration of the observations that have been made in these trials will provide a better understanding of both the possibilities and limitations of aptamers as therapeutics.


We thank the Department of Science and Technology, Govt. of India (IFA -13 LSBM-69) for financial support.

Funding: Department of Science and Technology, Govt. of India (IFA -13 LSBM-69)

Conflict of interest: None declared


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