INTRODUCTION:

Aptamers are DNA or RNA oligonucleotides that fold into specific three-dimensional structures and bind very firmly to target molecules. The name "aptamer" comes from the Latin root "aptus," which means "to fit."¹. Aptamers have a number of distinct qualities that make them desirable component for use in a variety of targeted cancer treatment applications. With strong binding affinities to their targets, aptamers have dissociation constants that are typically in the pico- to nano-molar range, which is similar to that of monoclonal antibodies^2,3. Generally, 2´-modified nucleotides, most often 2´-fluoro or 2´-O-methyl pyrimidines, are used to provide nuclease resistance to RNA aptamers^2,4. Aptamers are produced using in vitro chemical synthesis, it provides a number of advantages including decreased interbatch variability and possible cost savings when compared to biologic methods utilized in the production of monoclonal antibodies⁵. Aptamers are made by a process called "systematic evolution of ligands by exponential enrichment"^6,7.

A tertiary structured nucleic acid known as an aptamer has a high affinity and specificity for attaching to a target molecule⁸. In 1990, the Colorado University research team led by Larry Gold produced aptamers using the systematic evolution of ligands by exponential enrichment (SELEX) approach⁹. RNA and DNA aptamers are the two main categories of aptamers. Strong binding affinities for a range of targets are exhibited by both aptamer types^10-12. RNA aptamers have a unique secondary structure that allows them to bind to targets more tightly and precisely than other types of polymer molecules. Because ssRNA aptamers are often less than DNA aptamers, they may more easily penetrate cells and advantageously carry additional ligands or specifically tailored medications to the targets¹³. Aptamers' strong molecular target affinity may be applied in a number of ways. Aptamer-based cancer therapy is one of the most intriguing approaches. They can be used to medicine delivery, cancer diagnosis, and cancer signal blocking. A group of physicochemical methods known as the "drug delivery system" are capable of controlling the release and transport of pharmaceutically active compounds into cells¹⁴.

One of the leading causes of death worldwide is cancer. The current standard of care for cancer includes surgery, radiation therapy, chemotherapy, targeted therapy, hormone therapy, and immunotherapy^15,16. The 3D conformation of target molecules is recognized by aptamers, which are small, ssDNA or RNA possessing a significant binding affinity^17,18. Aptamers are being developed quickly for a variety of uses, including biosensors, clinical treatment, and diagnostics, ever since an in vitro method for accurately identifying an RNA species' ligand was first revealed by Ellington et al. and Tuerk et al.^19,20. Wet age-related macular degeneration is treated with the RNA aptamer pegaptanib sodium (Macugen), which has a high binding affinity for vascular endothelial growth factor (VEGF)²¹. including antibodies, aptamers can be used to accurately deliver therapeutic agents including chemotherapeutic medicines, therapeutic RNAs, poisons, and radioisotopes into cancer cells or tumors by acting as drug carriers, or aptamer–drug conjugates, or ApDCs. Additionally, they can be employed as therapeutic medications to specifically block signaling pathways associated with tumors²².

Aptamers:

One substitute antibody that is thought to be effective is termed aptamer, or "chemical antibody." Antigens are molecules that the host's immune system recognizes as foreign substances and reacts to in order to produce antibodies. The purified protein must typically be injected many times throughout this procedure²³. Small compounds are not considered suitable targets for the creation of antibodies since they do not provoke an immune response. Producing antibodies that specifically target hazardous chemicals is challenging since they are first produced by live animals. To create monoclonal antibodies, animals must be immunized, antibody-producing cells must be isolated, and myeloma cells must fuse with the immune system. After that, selecting hybridomas and producing antibodies are also required. Every step takes a long period, perhaps four to six months. Liquid nitrogen is commonly used to freeze and preserve hybridomas of antibodies. Some hybridomas are genetically unstable, whereas others can endure for a long time. Because nonproducing clones often outnumber producing clones, hybridoma cells have the potential to cease generating antibodies over time²⁴. However, aptamers are created in vitro, they may pick a larger variety of targets, and they address the drawbacks of the aforementioned antibodies (Table 1). Conventional Aptamer selection is typically a two- to three-month-long in vitro process, whereas the transfer process goes considerably more quickly. The aptamers are more advantageous than the antibodies in terms of size. IgG antibodies typically have a molecular weight of 150–170kDa, while aptamers with 30–80 nucleotides have a molecular weight of 12–30kDa (Table 1). Particularly when targeting dense tissues, the limited membrane permeability is demonstrated by the large size antibody^25,26.

Table 1. A comparison of antibodies and aptamers for cancer treatment

Parameters	Aptamer	Antibody
Composition	Nucleotides	Amino acids
Size	Small (5–15 kDa)	(Large) 150–180 kDa
Target	wide range	Immune related protein
Synthesis	simple (chemically synthesis)	Complicate (in vivo production)
Versatility tochemical modifications	High	Limited
Discovery time	~2–8 weeks	~6 months
Nuclease resistance	Sensitive (chemically unmodified)	Resistant
Tissue penetration	High	Low
Renal excretion	Rapid (chemically unmodified)	Slow
Immunogenicity	Low or absent	High

Development of Aptamers:

SELEX is frequently used to create aptamers focusing on a range of molecular or cellular targets^27,28. Proteomics and genetics have advanced over the last few decades, allowing for the mapping of the profiles of elevated biomarkers in a wide range of disorders, including malignancies. Numerous disease-related biomarkers, Prostate-specific membrane antigen (PSMA)³⁰, human epidermal growth factor receptor 2 (HER2)³¹, protein tyrosine kinase (PTK7)³², vascular endothelial growth factor (VEGF)²⁹, and epidermal growth factor receptor (EGFR)^33–35 have all been searched for in aptamers. Aptamer AS1411, which binds to nucleolin³⁶, was discovered by chance rather than by screening. Aptamer screening has been significantly enhanced by technological developments in chemical or enzymatic nucleic acid synthesis and amplification (e.g., PCR), sequencing, and bioinformatic analysis. One way to further facilitate the selection process is to use technology platforms such as capillary electrophoresis³⁷, microfluidics³⁸, and flow cytometry^39,40 to isolate aptamer candidate probes.

Proteins, peptides, and small molecules are examples of known molecular targets that may be used for aptamer screening. (Table 2). Aptamers for a number of biomarkers associated with disease, including interleukin 6 receptor (IL-6R)⁴¹, PSMA³⁰, and VEGF²⁹, have been found using this method. Since the generated aptamers can undoubtedly attach to the matching targets, employing aptamer screening using direct molecular targets has the obvious benefit of this approach. Using non-target compounds in a negative screening procedure can be used to guarantee the binding selectivity of aptamers by removing any undesirable ligands that also bind to these non-target molecules. SELEX has also been used with live cells, cell fragments, or even tumor tissuesusing aptamers as a filter against chemical targets present in tumor tissues or on cell surfaces^42,43. For example, cell-SELEX was created to find aptamers for particular target cells, including sick cells^44-48, using entire living cells³⁹. The prior idea about Cell-SELEX's molecular signatures is one of its most notable features. Additionally, aptamers for functional molecules on cell surfaces that to create functional conformations on cell surfaces, one may require cofactors or post-translational modifications. Additionally, cell-SELEX can be utilized to find biomarkers that have not yet been identified or whose functions in pathogenesis are unclear^43,49. It's interesting to note that aptamers have therapeutic applications in addition to being targeted ligands. Pegaptanib, also known as Macugen®, is an aptamer that inhibits VEGF165 and was authorized for the treatment of age-related macular degeneration (AMD) by the FDA²⁹.

Table 2. Examples of targets used for aptamer selections

Target for aptamer selection	Type of aptamer	KD	References
Ethanolamine	DNA	6–19 nmol/L	51
Ricin toxin	DNA	58–105 nmol/L	52
4,40 -Methylenedianiline	RNA	0.45–15 mmol/L	53
ATP	RNA	4.8–11 mmol/L	54
L-histidine	RNA	8–54 mmol/L	55
Sialyllactose	DNA	4.9 mmol/L	56
Moenomycin A	RNA	300–400 nmol/L	57
Bovine thrombin	RNA	164–240 nmol/L	58
Neurotensin receptor NTS-1 (rat)	RNA	0.37 nmol/L	59
HIV-1 nucleocapsid protein	RNA	0.84–1.4 nmol/L	60
TTF1	DNA	3.3–67 nmol/L	61
HGF	DNA	19–25 nmol/L	62
Leukemia cells CCRF-CEM	DNA	0.8–229 nmol/L	63

Figure 1. Diagrammatic illustration of the aptamer selection process using the protein-based SELEX method. Purified target molecules are usually used in the traditional SELEX approach, which also involves incubating the target molecule. The binding affinity is tracked during this cycle, which must be completed in several rounds, until a sufficient binding affinity is attained. Bioinformatics analysis is used to analyze sequencing data to isolate and identify high-affinity aptamers for the ligands by traditional cloning. Selectivity research to the particular target molecule comes after the aptamer selection procedure, and the compounds that are found have potential uses in diagnostic or therapeutic fields⁵⁰.

SELEX Methods:

The three primary processes of the traditional SELEX approach are selection, partitioning, and amplification. Up to 1015 different unique sequences are usually found in an oligonucleotide library is created prior to the selection⁶⁴. Every distinct sequence consists of random bases (20–50nt) that are encircled by two conserved regions for primer binding. Annealing primers is the process used to amplify PCR products. Target molecules are cultivated in the library for the specified amount of time during the selection process. The unbind and bound sequences are divided using several techniques following incubation. PCR (DNA SELEX) or reverse transcription PCR (RNA SELEX) are used to amplify the target-bound sequences. As a fresh sub-pool, the PCR products are used in the following selection process. Once the enriched sequences are sequenced, their capacities to bind are assessed further after multiple selection cycles. The hit rates are poor and the process of obtaining it usually takes weeks to months to find suitable candidates for aptamers. As a result, acquiring superior aptamers against relevant targets remains a bottleneck. To cut down on selection time and boost hit rates, a number of enhanced SELEX techniques have been put into practice (Table 3).

1. Negative SELEX:

In 1992, Ellington and Szostak proposed a novel technique termed negative SELEX⁶⁵. They incubated the library following three selection cycles, using agarose as a negative selection support for purification. From every pool, the non-specific binding sequences were eliminated. Compared to aptamers obtained without negative selection, the resulting aptamers had an affinity that was roughly ten times higher. Following that, this procedure was included in the majority of the modified SELEX to get rid of nonspecific sequences that were resulting from their attachment to the matrix of immobilization.

2. Counter SELEX:

Functions similarly to negative SELEX, with the exception that it employs comparable target molecules as incubation subjects. In order to improve the specificity of aptamers, Jenison et al. developed the counter SELEX technique in 1994⁶⁶. Counter SELEX differs from standard SELEX in that it includes an extra step that involves to successfully discriminate non-specific oligonucleotides, aptamers are incubated with structurally identical targets. In order to obtain more specific aptamers, this process has been drastically applied to various modified SELEX procedures^67-69. It should be mentioned that the primary distinction between negative SELEX and counter SELES is the incubation items they use.

3. Capillary Electrophoresis SELEX:

The traditional SELEX process requires a lot of labor and time to obtain aptamers; typically, it takes more than 15 rounds. Capillary Electrophoresis SELEX (CE-SELEX), a modified SELEX technique, was developed in 2004^70,71. CE-SELEX is a highly effective method of separation that distinguishes between target constrained sequences and unbound sequences based on differences in electrophoretic mobility. High affinity aptamer candidates can be chosen using this method, which also cuts down on the number of selection rounds from about 20 in traditional SELEX to just 1-4.

Many aptamers have currently been effectively selected using CE-SELEX^72,73. To speed up the procedure even more and lessen the bias in DNA amplification brought on by the PCR's repeated phases, modified selection procedures have been created. Non-SELEX is an alternative CE-based technique that selects an aptamer without amplifying it⁷⁴. The Non-Equilibrium Capillary Electrophoresis of Equilibrium Mixtures (NECEEM), an extremely efficient affinity method, is used in this technique to separate the oligonucleotides-target complex from the free oligonucleotides. The selection process takes an hour with non-SELEX, as opposed to several weeks or months with a standard SELEX. Aptamers have been effectively chosen using this strategy in opposition to bovine catalase⁷⁵.

4. Microfluidic SELEX:

In 2006, Hybarger et al. developed a prototype of microfluidic SELEX (M-SELEX) by combining traditional SELEX with a microfluidic device⁷⁶. The prototype includes a PCR thermocycler, pressurized reagent reservoir manifold, actuator valves, and reagent-loaded micro-lines for sample routing and selection. With this apparatus, they were able to effectively obtain an RNA aptamer against lysozyme.

Bead-based microfluidic SELEX^77,78, protein microarray-microfluidic chip SELEX⁷⁹, and Capillary Electrophoresis (CE) microfluidic SELEX⁸⁰ are a few of the modified microfluidic approaches that have been developed more recently to improve the effectiveness in selecting aptamers.

5. Cell SELEX:

Many aptamers that target pure proteins have been produced by in vitro SELEX; nevertheless, it is possible that these aptamers will not bind to the same proteins in cells under endogenous conditions or at endogenous amounts. Since Cell SELEX uses entire living cells as its target, there is a greater chance that the chosen aptamer to be applied directly in therapeutic and diagnostic application.

The cell SELEX approach was first developed by Daniels et al. in 2003, and they were able to successfully create a DNA aptamer against tenascin-C using the glioblastoma-derived cell line U251⁸¹. Presently, several enhanced cell SELEX methods are being created to increase the success rate of aptamer screening. Hicke et al. (2001) developed a hybrid SELEX that combines the advantages of cell-based SELEX with purified protein-based SELEX.

6. In Vivo SELEX:

The SELEX approach was created by researchers in vivo to generate tissue-penetrating aptamers in target animal models directly. Disorders, taking into account that aptamers identified in vitro might not necessarily be useful in vivo. The first attempt to identify aptamers inside a live organism's tumor was made by Mi et al. in 2010⁸³.

The mice were given an RNA library modified with 2'-fluoropyrimidine by Cheng et al. in an effort to find aptamers that could cross the blood-brain barrier⁸⁴. Aptamers with the ability to penetrate the parenchyma and adhere to brain capillary endothelia by employing this technique.

7. High-Throughput Sequencing (HTS) SELEX:

HTSmethod has been incorporated into the SELEX protocol recently. The first and foremost feature of HTS-SELEX is its ability to sequence the library during each selection phase. As a result, it takes less time to see enriched sequences at a much earlier stage. ChoMet al. carried out the first high-throughput sequencing implementation in SELEX in 2010. They discovered aptamers that, bind to the PDGF-BB protein with a specific Kd of less than 3 nM in three rounds⁸⁵. After five rounds of selection, Berezhnoy et al. (2012) similarly used HTS-SELEX to find IL-10 receptor-opposing high affinity aptamers⁸⁶. Since then, and particularly in the last five years, HTS-SELEX has been used to identify a number of aptamers against various targets^87-89.

APTASENSOR:

Aptasensors come in a variety of forms depending on the type of detection method used, such as fluorescence-based, colorimetric, electrochemical, etc ^{109, 110}. The response from the electrodes immobilized by aptamer is recorded in an electrochemical aptasensor (Figure 2). In addition, they are classified as sensors depending on the ampere analysis method, impedance, and cyclic voltammetry based on the detection of response signals upon target recognition.^{111, 112}

Figure 2: Different types of aptasensor

Aptamer-Mediated Targeted Therapies:

Chemotherapy, radiation, photodynamic therapy, and photothermal therapy are examples of traditional cancer treatment techniques that can have substantial adverse effects on patients because of their nonspecific toxicity. The idea of targeted therapy has been gaining traction as a way to reduce these adverse effects. Antibody-based medications are used in a number of clinical targeted cancer therapy techniques. The potential immunogenicity and high production costs of antibody-mediated therapy may restrict its practical applicability, despite its high specificity and low side effect rate. Recently, specialized drug delivery methods and targeted treatments based on oligonucleotide aptamers have been investigated as potential solutions to these challenges. These investigations showed that aptamer technology has many benefits protein-based antibody therapies, some of which are discussed in the following section.

Aptamer-drug conjugates (ApDC):

The process of directly conjugating aptamer sequences with medicinal drugs, either covalently or noncovalently, is known as ApDC and is a relatively basic model. One such example is the newly demonstrated improved therapeutic efficacy of chemotherapeutic medication doxorubicin (Dox), which is frequently used to treat a variety of cancers, when combined with an aptamer. The main way that doxes causes cytotoxicity is through intercalation into the nucleic acid structure at the preferred paired CG or GC sites. Which inhibits the multiplication of cancer cells. Dox has the ability to covalently attach to aptamer sequences by the use of a functional linker moiety, improving the stability of drug loading. Conversely, covalent conjugation is the most widely employed technique for aptamer-drug conjugation, particularly for agents whose intercalation would break aptamer structure or for which intercalation is not possible¹¹³. There is evidence that these aptamer-drug complexes that are covalently conjugated are substantially more stable than their noncovalently conjugated counterparts¹¹⁴.

Aptamer-nanoparticle therapeutics:

Aptamer-mediated drug delivery can have its potency and half-life of the medication increased using a desirable vehicle known as nanoparticles (NPs). NPs have unique atomic and molecular qualities determined by their materials in addition to their common characteristics, which include homogeneous dimensions and form for optimal biodistribution, a broad surface area for enhanced aptamer and medication loadingand biocompatibility for clinical applications. Liposomes and copolymers degrade naturally, but metal materials have remarkable magnetic and photothermal properties. As a result, NPs are widely utilized in controlled release and medication administration systems; a few instances are given below.

Copolymers and liposomes:

Copolymers and liposomes are more biodegradable and biocompatible than aptamers, conjugating them has great potential for targeted drug delivery. Aptamer-NPs bioconjugates were developed about ten years ago, as documented in the groundbreaking work of Farokhzad et al.^115,116. They used an anti-PMSA aptamer as a targeting molecule in their study, conjugating it with functional groups made of poly (lactic acid; PLA)-PEG or poly (lactic-co-gycolic-acid; PLGA)-PEG. PLA or PLGA assisted in the encapsulation and release control of the medication, whereas PEG extended the bioconjugate's circulation half-life.

An AS1411 aptamer was employed in a different instance to specifically target cancerous cells. Aravind et al. created PTX- and PLGA-lecithin-PEG-containing AS1411 aptamerNPs bioconjugates in this work as a breast cancer treatment¹¹⁷. Following optimization, the NPs showed better sustained drug release (60.93±3.4%) and high effectiveness of encapsulating (60.93±3.4%) as compared to the PLGA NPs. They were about 85.5 nm in size. These NPs increased the in vitro cell killing impact and were efficiently internalized by target cells, as was predicted¹¹⁸.

In order to treat prostate cancer, Dhar et al. coupled an RNA aptamer A10 that is specific to PSMA in a modified platinum [Pt (IV)]-based PLGA-PEG NP system¹¹⁹. The authors next looked into the biodistribution, effectiveness, tolerability, and pharmacokinetics of NPs. The findings demonstrate the prolonged systemic blood circulation length, elevated maximum tolerated dose, reduced renal toxicity, and improved in vivo anticancer activity of functional NPs^{119, 120}.

Metal nanomaterials:

Metal nanoparticles have outstanding optical, electromagnetic, stability, and biocompatibility characteristics, making them useful instruments in the creation of drug delivery systems. A unique metal nanoparticle (NP) called Apt-HAuNS-Dox was recently published. It consists of conjugated Dox, a functional hollow gold nanosphere (HAuNS), and an RNA aptamer (Apt) specific to CD30¹²¹.

Another application of gold nanoparticles (NPs) is when they are added to the photothermal treatment (PTT) approach while being exposed to near-infrared laser radiation. A study by Wang et al. reports that gold nanorods (AuNRs) have a surface coupling between two different aptamers, CSC1 and CSC13¹²². The conjugates that resulted were then used to target and specifically eradicate cancer cells; stem cells included.

Virus-like particles:

Natural nanomaterials called virus-like particles (VLPs) have several uses and can be employed in medicine delivery. Tong et al. first described a technique for creating VLP-aptamer conjugates in 2009¹²³. Up to sixty copies of the sgc8 aptamer were present on the surface of each MS2 bacteriophage capsidcoupled using an effective oxidative coupling technique. The conjugates of functioning sgc8 aptamer and VLPs demonstrated a robust ability to attach to target cells, which was then internalized and degraded within lysosomes.

In conclusion, it is possible to effectively improve utilizing copolymer, liposome, metal, and virus-like NPs to study the biodistribution, stability, and targeting affinity of aptamers. Furthermore, nanomaterials including silica, hydrogels, quantum dots (QD), and single-walled carbon nanotubes show promise as delivery systems for targeted treatments delivered by aptamer technology^124-126.

Gene therapy utilizing aptamers:

The efficacy of miRNA and siRNA molecules as cancer gene therapy has been well studied. They are potent gene silencing agents that belong to a novel class of gene-mediated medicines. However, because they don't exhibit cell or tissue specificity during in vivo distribution, their usage in clinical applications has been restricted. Thus, selective gene targeting can be efficiently achieved by combining siRNA/miRNA technology with aptamers that offer excellent targeting specificity.

Aptamer-siRNA chimeras have the potential to transport siRNA to target cells precisely, but systemic delivery is not without its difficulties. These include inadequate siRNA payload, unintended biodistribution, and brief biological half-life¹²⁷.

Immunotherapy using aptamers:

Immunotherapy is a relatively new idea in cancer treatment, because of its high specificity and low possible adverse effects, it has gained a lot of attention lately (Table 4). Notably, of all immunotherapy techniques, antibody-based medicines have received the greatest research. Antibodies have three main therapeutic mechanisms: increased complement-mediated cytotoxicity, antibody-dependent cell-mediated cytotoxicity, and phagocytosis or opsonization through the Fc functional region (ADCC). Oligonucleotide aptamers can perform therapeutic tasks by mimicking protein antibodies as chemical antibodies. Bruno et al. created a DNA aptamer-Fc combination to function as artificial antibodies in an initial investigation¹²⁸. The aptamer-Fc combination could be identified and internalized by macrophages, as the study unambiguously demonstrated, but no additional assessment of its therapeutic anticancer activity was carried out¹²⁸.

A bi-specific c-MET-CD16α aptamer was designed by Boltz et al. to enhance the the attraction of immune cells to a tumor. They used a combination of c-MET aptamer, which targets cancer cells specifically, and CD16α aptamer, which attracts natural killer cells that express CD16α. Following the optimization of both aptamer and DNA linker lengths, the two aptamers underwent conjugation. As a result, the target cells were killed and the natural killer cells were recruited by the resulting bi-specific aptamer¹²⁹. In order to modify the DNA aptamer, Xiong et al. added a PEG linker and a diacyl lipid tail at the 5′-terminaland was specific for K562 leukemia cells in another study.

Table 4. List of aptamers that modulate immune responses and are used in cancer immunotherapy

Aptamer	Application in Cancer Immunotherapy	Type of Tumor	Reference
CTLA-4	Targeting STAT3 siRNA	Lymphoma, Colon Cancer, Kidney Cancer, Fibrosarcoma	130
PD1	Immune-checkpoint blockade	Colon Cancer	132
TIM3	Immune-checkpoint blockade	Colon Cancer	131
IL10R	Immune-checkpoint blockade	Colon Cancer	132, 133
OX40	Costimulatory receptor agonist	Melanoma	134
CD28	Costimulatory receptor agonist	Lymphoma	135,136
CD40	Stimulatory receptor agonist	Lymphoma	137

Using aptamers for target cell biotherapy:

Numerous biomarkers and Certain biological activities, such as signal transduction pathways, are facilitated by cell surface receptors. As a result, their interactions with aptamers may have either antagonistic or agonistic effects on their particular physiological roles, which could lead to the death of cancer cells. Monovalent aptamers, particularly those that target cell surface indicators, typically lack the ability to activate downstream signaling cascades in a therapeutic context. On the other hand, downstream signaling is triggered by multivalent aptamers, which cause receptor multimerization.

The creation of a trimeric HER2 aptamer for use in A recent description of biotherapy in a human stomach cancer model was provided by Mahlknecht et al. By comparison with the monomeric HER2 aptamer, this trimeric aptamer greatly decreased the proliferation of cancerous cells in vivo and in vitro¹³⁸.

The anticancer efficaciousness of the trimeric HER2 aptamer was doubled when contrasted with a monoclonal antibody against HER2. The internalization and cytoplasmic translocation of the HER2 receptor caused by aptamer binding, as well as their subsequent destruction in lysosomes, were the molecular mechanisms involved¹³⁸.

CONCLUSION:

The advancements made in recent decades have demonstrated the wide-ranging potential of aptamers in the realm of cancer therapeutic research. Because of their strong affinity for target molecules, ability to improve therapeutic effects, and ability to reduce needless damage to non-cancer cells, aptamers have been developed and employed for several types of cancer therapies. A brief overview of some recent developments in aptamer-based cancer therapy systems is provided below. Aptamers provide a range of instruments for innovative medication delivery, therapy, and diagnosis to address various illnesses.

Aptamers can be used to selectively transport various treatments, such as chemotherapy, short hairpin RNA (shRNA), microRNA (miRNA), and small interference RNA (siRNA), The ligand (aptamer), linker, and warhead (drug) make up the three molecular components of ApDC, which can be arranged in a multitude of ways due to its general chemical and thermal stability and structural reversibility. Aptamers operate as recognition ligands that pinpoint illness sites and/or guide the administration of therapeutic medications that modify the biological function of the target biomarker. Thanks to developments in cancer medication delivery and combination technologies, aptamer and apt DCs are now a viable approach for targeted cancer treatment that reduces potential toxicity and increases therapeutic efficacy.

A fantastic tool for certain molecular pools is high throughput sequencingmore quickly and safely determining which aptamers work best against certain targets. Additionally, it simplifies the selection procedure evident during each round of consideration. In the near future, new tools and software that creation of aptamers with high affinity and specificity for therapeutic use will be made easier and faster by combining high-throughput sequencing and high-throughput binding studies.

In conclusion, new aptamers are being created more cheaply and efficiently thanks to SELEX technological advancements. In the near future, more aptamers should be able to be used for therapeutic and diagnostic applications (Table 5).

To get above their clinical application constraints, a lot of work needs to be done. Furthermore, the most noteworthy accomplishments of aptamers were their fusion with nanomaterials, which improved the diagnostic signal's specificity and enabled superior target cancer cell transport and detection. In conclusion, the aforementioned explanation demonstrated the adaptability and therapeutic utility of aptamers. Before going on to clinical use, a number of obstacles must be addressed, such as low biostability, short half-lives in vivo and an unclear method of drug release and endosomal escape. Additionally, more thorough studies are required to determine the safety of proteomics and genomics, the large-scale production technologies, prices, and organ toxicity. Notwithstanding these drawbacks, the speed at which chemistry and materials are developing propels our investigation of aptamer-based drug delivery systems with potent therapeutic benefits.

Table 5: Aptamer in clinical stages

Molecular Targets	Aptamer	Disease	References
HER2	Herceptamers	Cancer	139, 140, 141
EGFR	E07	Cancer	142
EpCAM	SYL3C, Ep1	Cancer	143
CTLA-4	CTLA4apt, aptCTLA-4	Cancer	144
PTK7	sgc8	Cancer	145
Nucleolin	AS1411	Cancer	146, 147, 148, 149
OS cell	LC09	Cancer	150
ALPL protein	Apt19S	Cancer	151
polynucleotide	Ep1	Cancer	152
PD-L1	aptPD-L1	Cancer	153
Tim-3	TIM3Apt	Cancer	154
IL-4Ra	cl.42	Cancer	155
CD28	AptCD28	Cancer	156

Future Perspectives:

Aptamers' unique properties low immunogenicity, safety, room-temperature stability, capacity to be coupled to other small molecules, and customization make them potentially useful in therapy. While the molecular mechanism of action of aptamers is still being completed and clarified, the primary problem that needs to be addressed is how to deliver them. As a result, research into creating carriers that can direct aptamers to certain locations is still ongoing. Modified aptamers have the potential to transport drugs to specific targets, and their synthetic origin ensures the repeatability of the experimental results at the outset and the clinical application in later stages of research and practice. Aptamer technology offers a lot of potential in the biomedical industry, but technical problems still need to be fixed in several areas.

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Received on 04.08.2024 Revised on 13.01.2025

Accepted on 16.04.2025 Published on 10.07.2025

Available online from July 17, 2025

Asian J. Pharm. Res. 2025; 15(3):274-286.

DOI: 10.52711/2231-5691.2025.00044

This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. Creative Commons License.

Cell surface biomarker	SELEX method	Aptamer	Applications	Reference
Alkaline phosphatase placental-like 2 (ALPPL-2)	Cell-SELEX	RNA	Pancreatic carcinoma diagnosis or therapy	90
AXL	Cell-SELEX	RNA	Inhibitory aptamer for AXL-dependent cancer	91, 92
B-cell activating factor receptor (BAFF-R)	Protein-SELEX	RNA	Targeting aptamer for BAFF-R-dependent cancer therapy	93
Carcinoembryonic antigen (CEA)	Protein-SELEX	RNA	Inhibition of CEA-mediated cancer metastasis	94
CD16α (FcγRIIIα)	Hybrid-SELEX	DNA	Targeting CD16α for immunotherapy	95
CD28	Protein-SELEX	RNA	Agonistic aptamer that enhances cellular immune response against lymphoma	96
CD30	Protein-SELEX or Hybrid-SELEX	RNA and DNA	Targeting or immunotherapy of T-cell lymphoma	97
CD44	Protein-SELEX	RNA and DNA	Targeting aptamer for cancer stem cells	98, 99
CD71 (Transferrin receptor)	Internalized-SELEX	RNA	Targeting of CD71-dependent cancer	100
CD124 (IL-4Rα)	Protein-SELEX	DNA	Blocking CD124 and inducing Myeloid-derived suppressor cells (MDSCs) apoptosis	101
CD133	Cell-SELEX	RNA	Aptamer that targets cancer stem cells	102
c-MET	Protein-SELEX	DNA	Targeting aptamer for c-MET-driven cancer	95
EGFR (ErbB1/HER1)	Cell-SELEX or Protein-SELEX	RNA	Antagonist for EGF-dependent cancer proliferation	103, 104
ErbB2/HER2	Protein-SELEX or Cell-SELEX or Internalized-SELEX	RNA and DNA	Targeting of HER2-driven cancer for therapy or diagnosis	105, 106, 107
E-Selectin	Protein-SELEX	DNA	Focusing on tumors with elevated E-Selectin expression in order to diagnose or treat them	108