Int J App Pharm, Vol 16, Issue 1, 2024, 33-50Review Article

APTAMERS: NANOMATERIALS AS A POTENTIAL AGENT FOR ANTIVIRAL THERAPEUTIC DRUG DELIVERY DEVELOPMENT: A SYSTEMATIC LITERATURE REVIEW

MUTHADI RADHIKA REDDY1*, SHIVA KUMAR GUBBIYAPPA2, SHAIK HARUN RASHEED1, KONDAPURAM PARAMESHWAR3

1*Department of Pharmaceutics, Guru Nanak Institutions Technical Campus-School of Pharmacy, Hyderabad, India. 2Department of Pharmaceutics, Gitam School of Pharmacy, GITAM Deemed to be University, Rudraram, Hyderabad, India. 3Department of Pharmaceutics, Guru Nanak Institutions Technical Campus-School of Pharmacy, Ibrahimpatnam, Hyderabad, India
*Corresponding author: Muthadi Radhika Reddy; *Email: muthadiradhika@gmail.com

Received: 07 May 2023, Revised and Accepted: 08 Sep 2023

ABSTRACT

Chemotherapeutic experts have been utilised to cure a variety of disorders, but their practical application is restricted due to their regrettable selectivity and outrageous fundamental optional effects. Short single-stranded DNA or RNA oligonucleotides known as aptamers are released from randomised libraries and have strong propensity and differentiation towards targets like antibodies as well as characterised structures and ties to targets like proteins. They commonly suppress protein interactions while restricting proteins, which may elicit positive effects like threat. Aptamers have recently demonstrated their amazing promise for use in medicines, biosensors, and bioimaging thanks to a number of advantages, such as minimal immunogenicity, simplicity of giant degree blend, low pack to-bunch collection, genuinely substance modification, and programmability. At any rate, the steady for the most part accomplishment speed of aptamer is far from being brilliant, despite everything needs to overwhelm the gigantic obstruction in propensity, constancy for utilitarian application, explicit illness cell affirmation. The sensible method of controlling the binding execution of aptamers and dealing with their show in the practical application is of great significance and these single-abandoned DNA or RNA aptamers could outline with astoundingly poisonous chemotherapy drugs, hurts, strong RNAs or different particles as novel aptamer-drug structures, which are prepared to do endlessly out working on the obliging plentifulness and decreasing the critical danger of solutions and have unprecedented possible in living spaces for appointed ailment treatment. In this survey, we have extensively covered and summarised the ongoing improvements in the aptamer-drug structure philosophy for designated drug transport in the assessment methodologies of aptamers for unambiguous disease biomarkers. A modified strategy utilising aptamers could be a reliable system for quick and precise advancement of biopharmaceutics for use in infection-related treatment, especially in light of the enormous advances in modernised thinking for protein and RNA structure conjectures. Additionally, the likelihood of future conception is also summarised.

Keywords: Cancer, SELEX, Targeted drug delivery, Nanoparticle, Therapy, Aptamer

© 2024 The Authors. Published by Innovare Academic Sciences Pvt Ltd. This is an open access article under the CC BY license (https://creativecommons.org/licenses/by/4.0/)
DOI: https://dx.doi.org/10.22159/ijap.2024v16i1.48266 Journal homepage: https://innovareacademics.in/journals/index.php/ijap

INTRODUCTION

For the best clinical applicability, proper evaluation must be followed by effective treatment. Researchers have been actively pursuing the specific delivery of anticancer drugs to malignant development cells for a long time. Nanoparticles may more efficiently encapsulate and deliver anticancer drugs to tumour-growing tissue [1]. Despite this, nanoparticles as such are not specific to cancerous development cells; rather, the increased permeability and retention (EPR) effect of the cancer tissue is what causes nanoparticles to aggregate, particularly in disease locations [2, 3]. However, if ligands with the ability to recognise malignant growth cells specifically could be added to nanoparticles, they would actually want to target and deliver cargoes to disease cells specifically, greatly increasing the restorative record (expanding helpful viability while reducing harmfulness). Aptamer is one of the molecules that have been studied so far to explicitly functionalize nanoparticles for focusing [4]. Small single-stranded DNA or RNA oligonucleotides known as aptamers, have the ability to generate secondary and tertiary structures. Similar to antibodies, which are essentially made of nucleic acid with high affinity to specific targets like ions, entire cells, peptides, proteins, bacteria, viruses, and other cellular targets, etc., antigens are separated from randomised libraries and exhibit high affinity and specificity towards targets. These nucleic acid aptamers, which typically vary in size from 20 to 80 nucleotides, first appeared in the 1990s and exhibit binding properties [5, 6]. The Aptamer, a medicinal drug created by Nexstar and NeXagen, exhibits perfect analogies to antibodies. NX1838, now known as Macugen (Pegaptanib sodium), was the first Aptamer to be used in a clinic setting (and the first FDA-approved Aptamer). NX1838 functions as a vascular endothelial antagonist [7, 8].

Due to aptamers' remarkable potential, such as their potent anti-tumor activity, excellent circulation stability, biocompatibility, multimodal diagnostic functionalities, high loading efficiency, and ability to treat bacterial or viral infections, the field of aptamers research is expanding [9]. The issues of aptamer degradation, metabolic clearance, renal filtration, regulation of the duration of action, cross-reactivity, and irreversible tissue uptake remain despite aptamers' potential for theranostic and bioimaging applications [10]. Systematic Evolution of Ligands by Exponential Enrichment (SELEX) is an in vitro selection process for aptamers that is used to find the best aptamer for a given target. It comprises of the three main phases of library formation, binding/separation, and nucleotide amplification [11]. The use of aptamer-conjugated nanoparticles (NPs) and their theragnostic applications in a variety of diseases, such as oncology, inflammatory, and viral diseases, with their in vitro selection procedure and their applications along were discussed, are presented in this review.

In vitro screening of aptamers with drug delivery potential

Systematic Evolution of Ligands by Exponential Enrichment (SELEX), an iterative process of exponential enrichment, is typically used to manufacture aptamers. In this procedure, aptamers are screened from a randomised ssDNA or RNA library. It is utilised to choose the aptamer from roughly 1012-10-15 combinatorial oligonucleotide libraries [12, 13] that has a high affinity towards the particular target. It consists of the three main phases depicted in fig. 1, which are the creation of the library, binding/separation, and nucleotide amplification. As indicated in table 1, SELEX methods based on proteins, cells, and animal models are currently often used to select the aptamers with drug delivery potential.

Fig. 1: Schematic illustration of SELEX protocol for aptamer identification (Reprinted from [13] with permission (RSC 2015))

Table 1: Comparison of the advantages and disadvantages between three SELEX approaches

Model Protein-based selex Cell-based selex In vivo selex References
Target Purified proteins Live cells CDX or PDX models [33]
All types of proteins Membrane protein Membrane protein [33]
Advantages Wide range of target Recognition of target with native form; without the prior knowledge about target proteins High biostability; high specificity; suitable for cancer metastasis model; capable of crossing the blood-brain barrier [34, 35]
Disadvantages Time-consuming, vague, and ineffective in recognising targets in their natural conformations Time consuming; failure for in vivo use High cost [33, 39, 40]

The food and drug administration approved only one aptamer (Pegaptanib, Macugen®) to date for the treatment of age-related macular degeneration (AMD) [15]. Pegaptanib is an RNA aptamer that specifically recognises and inhibits the human vascular endothelial growth factor (VEGF165) with high affinity (Kd 50 pM) [16]. Current studies describe the developments of these aptamer nanomedicines in clinical trials [17, 18]. Other therapeutic aptamers are currently being assessed in a variety of clinical trials, spanning from phase one to three. Here, a variety of SELEX techniques have been used to produce aptamers with efficient cell-targeting and internalising capabilities. The majority of these methods reflect one of two basic strategies: classic protein-based SELEX for binding to isolated membrane proteins or live cell-based SELEX [19, 20]. Several of the most used aptamers for cancer antigens are listed in table 2.

Table 2: Aptamers that bind cell-surface markers selected by protein-SELEX or cell-SELEX

Aptamer library Name of the aptamer Biomarker Type of SELEX References
RNA, DNA FB4, GS24 (DW4) mTfR Protein-SELEX [107]
2’F-RNA A9, A10 PSMA PSMA Protein-SELEX [106]
DNA Sgc8 PTK7 Cell-SELEX [109]
2‘F-RNA E07 EGFR Protein-SELEX [110]
Thio-DNA TA1-TA6 CD44 Protein-SELEX [111, 104]
2‘F-RNA c2, Waz CD71 (hTfR) Hybrid SELEX1 [115]
DNA AS1411 Nucleolin screening of G-rich oligos in cell lines [117, 118]
2’F-RNA GL56 Insulin receptor Cell-SELEX [119]
2’F-RNA B1, C1, E1 HER2 Cell-SELEX [113]
DNA C10, C10.36 CD19 (+) Burkitt lymphoma Cell-SELEX [121]

Hybrid SELEX = combination of protein-and cell-based SELEX.

As a result, with the introduction of SELEX, the invention technique has changed and improved in terms of efficiency and time-cost optimisation. Aptamers have had a lot of success, but they have some drawbacks that prohibit them from being widely used in many applications, especially in the biomedical sciences. The primary issue is aptamer degradation by nucleases in biological media. Modified nucleotides before or after the SELEX round, mirror image aptamers, and aptamer displacement screening are frequently employed to address this problem.

For instance, altering the 20-amino pyrimidine nucleoside sugar position, 20-fluoropyrimidine nucleosides [20-23], 20-O-methyl purine, and 20-O-methyl pyrimidine nucleosides or 30-and 50-nucleotides, located L-ribose or L deoxyribose in oligonucleotide backbone and displace aptamer with low-molecular-weight compound from the binding site of a target molecule, improve pharmacokinetics of the aptamer in blood. Regarding the second issue, increasing the size of the aptamer by conjugation with polyethylene glycol (PEG) and renal aptamer filtration is an effective technique to lengthen the bloodstream circulation period. The usage of polycationic biopolymers like porphyrin and converting an inactive aptamer to an active form are the most popular solutions to the third challenge linked to controlling the activity duration of aptamers [24, 25]. Furthermore, Cell-SELEX and in vivo SELEX negative selection [26], automated SELEX and CE–SELEX were used to avoid aptamer generation with purified target molecules, cross-reactivity of aptamer, and automation of aptamer generation limitations, respectively [27], SELEX has often been carried out on pure proteins, and it may be difficult to purify cell surface receptors in their correctly folded and changed conformations as a result, not many aptamers that bind cell surface receptors have been produced. Most surface receptors are actively internalised in response to ligand contact, and all cell surface proteins cycle intracellularly to some extent. Subsequently, various payloads have been conveyed into cells utilizing aptamers that tight spot cell surface receptors displayed in table 3.

Table 3: Cell surface protein aptamers and their applications

Receptor name RNA/DNA Choice technique Delivery usage Reference
Mucin-1 (MUC-1) DNA Recombinant peptides

Photodynamic therapy (PDT)

Radionuclide delivery

 [123]
Prostate-specific membrane Antigen (PSMA) RNA Purified extracellular domain of PSMA siRNA delivery, cytotoxin delivery, Chemotherapeutic drug delivery and cellular imaging [124-128]
Immunoglobin heavy mu chain (IGHM) DNA Cell SELEX using Burkitt’s lymphoma cell line (Ramos) Micelle nanoparticles for drug delivery [129]
Tenascin-C (TN-C) RNA Purified TN-C In vivo tumor imaging [130]
Nucleolin DNA Not applicable Photodynamic therapy (PDT) tumor imaging [156]
Protein tyrosine kinase-7 (PTK7) DNA Cell SELEX using T-cell acute lymphoblastic leukemia (ALL) cell line Chemotherapeutic drug delivery [147]
gp120 RNA Purified recombinant gp120 siRNA delivery [141]
Epidermal growth factor receptor (EGFR) RNA RNA Purified extracellular domain of EGFR Nanoparticle delivery [155]
Transferrin receptor (TfR) RNA/DNA Purified extracellular domain of mouse TfR Protein targeting to lysosome [164]

CE microfluidic chips

The target molecules are incubated with a library of ssDNA. Binding sequence separation is accomplished via capillary electrophoresis. By using PCR to purify and amplify binding nuclear acids, an enriched pool of ssDNA is produced that is ready for additional rounds of selection. After two to four rounds of selection, high-affinity aptamers are frequently obtained [30, 31]. Additionally, the CE-SELEX approach has a higher partitioning efficiency than the conventional SELEX method, which reduces the number of rounds of SELEX to one to three [32]. The CE-SELEX typically takes less than an hour to incubate at room temperature. The targets' activity is also maintained during the brief incubation period [33].

Sol-gel microfluidic chips for screening of aptamers

A microfluidic device is used to incubate a library of ssDNA with protein sol-gel arrays in order to effectively select ssDNA aptamers against target molecules [34]. The number of selection cycles required to manufacture high-affinity aptamers was significantly decreased thanks to the sol-gel microfluidic devices. As a result, it may help enhance the selection of aptamers for these particular proteins and enable the separation of aptamers unique to many of the target proteins [35].

Magnetic-bead-based microfluidic chips for screening of aptamers

The random ssDNA library is first incubated with target proteins attached to magnetic beads in the microfluidic selection procedure. After incubation, the microfluidic chip performs the partitioning process to separate the target-bound aptamers from the unbound nuclear acids [36]. To continually elute weakly-and unattached nuclear acids from the microfluidic chip, strict washing conditions are established in the microchannel [37]. The external magnets are taken out following the separation, and the beads containing the chosen aptamers are liberated from the apparatus. On the chip, the full separation procedure, including bead elution, washing, and trapping, is carried out. The chosen Aptamers are then amplified by PCR. The SELEX technique has become more effective because to the use of magnetic beads to choose aptamers in a microchannel [38].

Cell selex

The cell SELEX involves the same procedures as a regular SELEX, including incubation, partitioning, and amplification. Both positive and negative selection are part of the crucial cell SELEX process. Negative selection is a crucial phase in the process since it helps the candidate Aptamer become more specific by removing the sequence that binds to healthy cells [39]. Various modified cell SELEX procedures have been developed over the past few years in an effort to increase the efficacy [40] and enrich the aptamer screening depicted in fig. 2.

Fluorescence-activated cell sorting SELEX [FACS-SELEX]

In this method, a cytometry device is used to separate the cell [target] which is bound to Aptamer, from the unbound Aptamer, which is based upon the principle of fluorescence and scattering. This technique developed in which the isolation and identification of the bound Aptamer to the target is carried out by using FACS device [41].

Cell internalization SELEX

The primary benefit of this approach, which is supported by numerous research, is that the aptamer is carried inside the cells as well as bound to the cell surface [42-44].

Fig. 2: Schematic illustration of the cell-SELEX. This procedure consists of four main steps for each round of selection: (i) counter-selection by incubating the nucleic acid library with negative cells (green cells) that do not express target antigens, (ii) a positive selection by incubating recovered unbound sequences with positive cells (tan cells) expressing cell-surface antigens (depicted in blue), (iii) recovery of target-bound sequences, and finally (iv) re-amplification of recovered species. (Reprint with permission from (44) Biomedicine 2017)

3D cell SELEX

This process, which is utilised to create the proper Aptamer against the target molecule, combines the three-dimensional [3D] cell culture and cell SELEX methods. Since 3D cell culture replicates or offers the natural cellular environment in which the cell grows, it is used in this method because it creates a physiologically acceptable setting that will aid in the improvement of the research and drug discovery processes. With the aid of magnetic levitation technology, the two-dimensional cell cultures are transformed into the three-dimensional cell structures [45].

Ligand gaided selection [LIGs]

Using this technique, an aptamer is created against a target cell's expressed epitope of interest [46].

Cross over SELEX

The Hicke's laboratory created this technique with the primary goal of creating aptamers with increased efficiency and avoiding creating aptamers against molecules or biomarkers expressed on target cells [47].

Counter SELEX

Negative SELEX and counter SELEX serve comparable functions, however, counter SELEX uses related target compounds as incubation subjects. Jenison et al. created the counter SELEX technique in 1994 to increase the specificity of aptamers [48]. Counter SELEX, in contrast to conventional SELEX, includes an additional phase that involves using structurally-similar targets to incubate with aptamers in order to successfully distinguish non-specific oligonucleotides [49, 50]. It should be noted that the usage of various incubation items is the primary distinction between counter SELES and negative SELEX [51].

Capillary electrophoresis SELEX

In general, it takes about more than 15 rounds to obtain aptamers using the conventional SELEX method, which is labor-intensive and time-consuming. In 2004, a modified SELEX method called capillary electrophoresis SELEX (CE-SELEX) was developed [53, 54]. CE-SELEX separates the target bounded sequences from unbound sequences by the difference in electrophoretic mobility, which is a highly efficient separation method.

In vivo SELEX

An in vivo-based SELEX technique was created by researchers to produce tissue-penetrating aptamers inside of animal models of the target disorders. Mi et al. attempted to choose aptamers inside a tumour of a living organism for the first time in 2010 [55]. With the exception of the selection target, the process for this in vivo SELEX is comparable to that of regular SELEX. In mice suffering intrahepatic tumours, a library of RNA aptamers modified with 2'-fluoropyrimidine was administered into the tail vein. The aptamers were then taken out of the liver tumours, amplified, and injected again into more mice carrying the same tumour. They were successful in choosing aptamers against the RNA helicase and p68 that had Kd values in the nano-molar range. Cheng et al. injected a 2'-fluoropyrimidine-modified RNA library into the mice in an effort to find aptamers that can cross the blood-brain barrier [56]. Fig. 3 shows the aptamers that were discovered using this method to adhere to brain capillary endothelia and enter the parenchyma.

Fig. 3: A) Schematic representation of the SELEX method. An initial DNA library (of typically 1014 molecules) is incubated with the solid support-bound target. Unbound DNA molecules are discarded while the active species are recovered, amplified by PCR, and injected into subsequent rounds of selection. The stringency of the selection protocol can bemodulated by altering physicochemical parameters such as concentration, pH, temperature, or buffer composition. At the end of the protocol, the enriched population is sequenced and the individual aptameric sequences evaluated for their capacity at binding to the target (10). B) Cell-process: Step 1 involves counter selection by incubating the RNA library with negative cells that do not express the target protein. Step 2 involves positive selection by incubating recovered unbound sequences with positive cells expressing the target protein. Step 3 involves recovery of target-bound sequences. Step 4 involves re-amplification of recovered species and generation of a new RNA pool for the next selection round. In vivo process: After intravenous administration and circulation of an RNA library in the animal model (step 1), the tissue or organ of pathological interest is harvested (step 2) and the bound sequences are extracted (step 3). Subsequently, the recovered RNA sequences arere–amplified to make a new RNA library for the next selection cycle (step 4) (30). Copyright 2018, reprinted with permission from Elsevier, (10) and Copyright 2017, Macmillan Publishers Limited, part of Springer Nature (30)

High-throughput sequencing SELEX

Up until now, traditional sanger sequencing analysis has been the primary technique for determining each individual sequence in the final enriched library. The finished library typically contains thousands of sequences, making it challenging to determine which one is the greatest aptamer. Additionally, the sequences with the highest affinity and specificity are not usually the ones that are most numerous in the final selection phase. The SELEX technique recently adopted High-Throughput Sequencing (HTS) technology [57, 58]. The first feature of HTS-SELEX that stands out is the ability to sequence the library during each round of selection. As a result, enriched sequences are evident at a much earlier round, saving time. Additionally, fewer selection rounds prevent the potential over-selection-related PCR bias [59]. Cho M et al. carried out the first high-throughput sequencing application in SELEX in 2010. Within three rounds, they found aptamers with Kd 3 nM that specifically bind to the PDGF-BB protein. After five rounds of selection, Berezhnoy et al. (2012) also used HTS-SELEX to find high-affinity aptamers against the IL-10 receptor [60, 61].

Aptamer based sensor

The aptasensor, which acts as a recognition site and is present over the aptamer, can be created using a variety of techniques and methodologies [62].

Electrochemical biosensors

The electrochemical aptasensors' primary benefits include their high sensitivity, compatibility with cutting-edge microfabrication techniques, intrinsic miniaturisation, and low cost. The manufacturing of electrochemical aptasensors employs a variety of techniques. Some of these include DPV (Differential Pulse Voltammetry), ETS (Electrochemical Impedance Spectroscopy), ECL (Electrogenerated Chemiluminescence), and Potentiometry using ISEs (Ion Selective Electrodes) [63-68]. It is simple to employ aptamers, which are oligonucleotides, as targeted agents in medicine administration [69] and even in the creation of biosensors to identify infectious agents. Aptamers can also target viral proteins linked to various viral infection phases, as illustrated in table 4.

Table 4: Summary of aptamers used in inflammatory and viral disease

S. No. Aptamer Target Action Reference
Spiegelmers NOX 2149 ORL-1R Decrease in pain and stress [66]
DEK-binding Nuclear chromatin protein DEK Juvenile idiopathic arthritis [64]
20–NH2-30-ligand (RNA) IFN-a Immunoregulatory [69]
SE RNA Hepatitis C virus NS3 Viral proliferation in chronic hepatitis [71]
DD7, ED1 (RNA) hNE-specific ligand A Anti-inflammatory [69]
LIGAND 1.1 HIV-1 RT Anti-HIV [64]
Aptamer M. G (RNA) Acetylcholine receptors Control of myasthenia gravis [77]
CD4-specific aptamer 14 (RNA) Antigen-presenting cells Immunosuppressant [79]
ADR58 (RNA) gp130 receptor Control of rheumatoid arthritis [66]
D7, ED1 (RNA) hNE-specific ligand Anti-inflammatory [77]
DEK-binding Nuclear chromatin protein DEK Juvenile idiopathic arthritis [78]
IGEL1.2 and D17.4 (DNA) Human IgE Antiallergic response [78]

Optical biosensors

Fluorescence-based APTA sensors

A fluorophore or nanoparticle that has been combined serves as the common foundation for this optical biosensor. For example, the cocaine-specific Aptamer was able to detect the target by using FRET [Fluorescence Quenching/Fluorescence Resonance Energy Transfer signal between fluorescence and DABCYL moiety [A Quencher] in this method for the fluorescence detection [74].

Colorimetric-based APTA sensors

This approach uses a unique color-changing reagent known as a colorimeter, such as AUNPs or another polymer [75]. In addition to the sensor mentioned above, other sensors, such as those used for SAW (Surface Ascoustic Wave), QCM (Quartz Crystal Microbalance), and microchannel cantilever sensor, have been utilised in conjunction with other types of analytical equipment [76-81].

Characterization of aptamers kinetics

Isothermal Titration Calorimetry (ITC), an approach based on thermodynamics [82], Microscale Thermophoresis Using surface plasmon resonance (SPR) technology, it is possible to characterise the aptamer and its target's affinity and kinetic characteristics in high throughput, real-time, and label-free manners [83]. The laser-based technique known as flow cytometry is frequently used to identify the binding properties of aptamers and entire cells. It can characterise the binding properties of aptamers and targets [84]. A fluorescent dye, such as FITC dye, is used to label the aptamer library before it is combined with the target cell. The level of fluorescence reveals how well the aptamer binds to the selected cell [85]. The ability to examine how aptamers bind to their targets is one of flow cytometry's most notable features.

Diagnostics or bio-sensing potential of aptamers

Bruno et al. created the first aptamer utilised as a diagnostic tool in 1999. To find anthrax spores, they used the aptamer chosen against Bacillus anthracic spores [86]. Aptamers have been extensively used to diagnose ophthalmology, cardiovascular illnesses, and cancer diseases up to this point. For instance, Wan et al. used aptamers against the common oncogene epidermal growth factor receptor (EGFR), which is overexpressed in many cancer types, to recognise cancer cells [87]. They immobilised anti-EGFR RNA aptamers on the surface of modified glass and discovered that these aptamers could highly precisely and sensitively trap glioblastoma cells. These findings suggested that aptamers could be employed for the early detection of cancer metastasis or for the detection of tumour cells. Two domains are present in the aptamer-based diagnostic tools: the targeting domain (aptamer) and the signalling domain (radionuclide or fluorescence). A DNA aptamer (XL-33) with a Kd value of 0.7 nM that might target metastatic colon cancer cells was chosen by Li et al. [88]. To visualise the cancer tissue, they further shortened the aptamer and added fluorescein amidite (FAM) to it [89]. Some example aptamers are sequentially given in table 5 to illustrate the features of recently created aptamers as diagnostic tools for biomedical usage.

Table 5: Examples of recently developed aptamers for the diagnosis of human diseases

Name Target Kd (nM) Sensitivity Specificity Reference
Cancers
SYL3-C Solid cancer epithelial cell adhesion molecule (EpCAM) 22.8 60% 100% (n = 3) [68]
XL-33 Metastatic colon cancer cells (SW620) 66.7% (n = 18 non-metastatic colon cancer tissues) 0.7 81.7% (n = 71) metastatic colon cancer tissues) 66.7% (n = 18 non-metastatic colon cancer tissues) [66]
LXL-1 Metastatic breast cancer cells (MDA-MB-231) 44.0 76% (n = 34) 100% (n = 8 cancer cell lines) [93]
GMT3 Glioblastoma multiforme cells (A172) 75.3 - 87.5% (n = 8 cancer cell lines) [69]
yl19 Cholangiocarcinoma cells (QBC-939) 42.4 - 100% (n = 6 cancer cell lines) [65]
Cardiovascular diseases
Myo 040-7-27 Myoglobin 4.93 10 pm - [27]
Infectious diseases
2008s Plasmodium falciparum lactate dehydrogenase 42–59 57 ng/ml No human LDH recognition [71]
LmWC-25R and LmHSP-7b/11R Leishmania promastigote and hydrophilic surface protein - 100 ng (parasite protein) - [72]

Because of its ease of use, sensitivity, and abundance of fluorophores and nucleic acid quenchers, allosteric aptamer-based fluorescence resonance energy transfer (FRET) for the detection of molecular targets represents a superb option. According to a study, a secondary antibody tagged with an easy-to-measure dye or enzyme can be linked to an RNA aptamer identified against the biomarker for inflammation, sepsis, and tissue necrosis known as C reactive protein [90, 91]. With an aptamer-based sandwich immunoassay, it is possible to identify C reactive protein in serum samples from both high-risk (>500 mg/l) and low-risk (1e3 mg/l) patients [92]. Sandwich immunoassays based on aptamers have evolved into high-throughput microarray-based diagnostics through innovation and the development of automated high-throughput aptamer separation [93, 94].

Rationale therapeutics of aptamers targeted drug delivery

The dynamic application of nanoparticle-aptamer technology goes beyond diagnostics to include targeted medicine administration. Delivering medications to cancer cells specifically using nanoparticle aptamer bioconjugates, is one of their most popular applications. Aptamers are being developed as therapeutics for a number of diseases, including cancer treatment, the prevention of Alzheimer's disease-related proteins [95, 96], protection against the pathological prion protein isoforms that cause Creutzfeldt-Jakob disease [97, 98]. Mycobacterium tuberculosis, and the treatment of hepatitis C virus (HCV). The most advanced aptamer in the potential treatment of cancer is AS1411. AS1411 aptamer binds nucleolin on the surface of cancer cells and induces apoptosis [99-102].

An further aptamer known as SM20, which was identified against the plasminogen activator inhibitor-1, has shown in vitro therapeutic promise as an antimetastatic drug and may be utilised as an adjunct to conventional chemotherapy for breast cancer [103]. Aptamer nanomaterials have also emerged as promising nanoplatforms for accurate ovarian cancer diagnosis by recognising pertinent biomarkers in the serum and on the surface of tumour cells. Aptamers have been recently isolated for the potential treatment of other cancers such as glioblastoma, T cell leukaemia, and epithelial cancer cells in the breast, colon, lung, ovaries, and pancreas [104, 105]. Additionally, for efficient ovarian cancer inhibition by target protein blocking on tumour cells and focused administration of different therapeutic agents, a list of diagnosis agents and treatments is provided in table 5.

Aptamer-short molecule conjugated systems

An aptamer-doxorubicin physical conjugate was created by Bagalkot et al. because doxorubicin can intercalate into aptamers [106]. They employed a prostate-specific membrane antigen (PSMA)-targeting 2'-fluoropyrimidine-modified RNA aptamer, which is mostly expressed on the surface of human prostatic adenocarcinoma (LNCaP) cells. They demonstrated that this combination has great specificity and affinity for PSMA-expressing LNCaP cells. The sgc8c DNA aptamer, which particularly targets T-cell acute lymphoblastic leukaemia cells, and doxorubicin were covalently joined together by Huang et al. [107]. As a result, the cellular toxicity of the sgc8c-Dox conjugates to non-target cells was decreased. A doxorubicin conjugated aptamer complex (TLS11a-GC-Dox) against HepG2 cells was recently created by Deng et al. [108].

Aptamer-nanomaterial conjugated systems

For targeted drug delivery, Luo et al. created an aptamer/hairpin DNA-AuNPs combination as a smart drug carrier. The protein tyrosine kinase 7 (PTK7) DNA aptamer sgc8c was initially assembled onto the surface of the AuNPs. Then, they added more doxorubicin, an anticancer medication, to the hairpin DNA's repeating d (CGATCG) sequence on the surface of the AuNPs. Such a conjugated compound might increase anti-tumor activity while reducing toxicity. A gold nanostar core and an AS1411 anti-nucleolin aptamer make up the nanoconstruct that Dam et al. created [109, 110]. Such a nanoconstruct accumulates five times more in invasive breast cancer tumours than in fibrosarcoma tumours in a tumor-specific way and without any acute harm. In 2009, Cao et al. created the first aptamer-liposome delivery method [111]. The anti-nucleolin aptamer sequence was originally given a 12-thymine spacer at the 3' end. The chemotherapeutic drug cisplatin (to induce anti-proliferation activity) or the hydrophilic dye calcein (to monitor internalisation) were encapsulated into the liposome core after the spacer was further attached with a cholesterol tag for the immobilisation on a PEGylated liposome hydrophobic surface [112, 113]. They discovered that this combination could administer cisplatin in a way that was particular to cancer cells. Other nanomaterials being utilized in blend with aptamers for designated organization incorporate block polymeric nanoparticles, carbon nanotubes, gold-attractive nanoparticles, Quantum Spot (QD) serum egg whites nanoparticles, and dendrimers displayed in table 6.

5.3. aptamer-RNA conjugated systems

For the purpose of delivering these functional RNAi to the target site, aptamers to be associated with microRNA (miRNA), small interfering RNA (siRNA), and short hairpin RNA (shRNA) have been widely investigated. Mcnamara et al. proposed the first aptamer-siRNA chimaera in 2006 [114]. They covalently joined therapeutic siRNAs that target the two survival genes PLK1 and BCL2, which are overexpressed in many patient malignancies, to an RNA aptamer against human PSMA (dubbed A10). The "GL21. t-let" aptamer-miRNA conjugate was created by Esposito et al. [115]. The oncogenic receptor tyrosine kinase Axl and the human let-7g miRNA, which functions as a gene-silencing moiety, could both be selectively bound to and antagonised by the aptamer (GL21. t) [116]. To target the suppression of Nonsense mRNA-Mediated Decay (NMD), Soldevilla et al. first discovered high-affinity aptamers against CD40 and then coupled CD40 agonist aptamer-shRNA chimaera. Additionally, Fernando Pastor et al. [117] demonstrated that costimulatory ligands can be delivered to tumour cells in situ by bi-specific oligonucleotide aptamer conjugates (4-1BB aptamer ligand-PSMA aptamer conjugates).

The advantages of using aptamers to functionalize nanomaterials for combination therapy

Aptamers are particularly ideal molecules to functionalize nanoparticles for actively targeted administration due to their excellent binding specificity and affinity as well as a number of other advantageous characteristics. Although none of the aptamer functionalized nanoparticles have yet been used in a clinical trial or application, multiple preclinical and animal studies have already shown their efficacy in the targeted delivery of anticancer medicines The proof-of-concept study of employing the aptamer to functionalize nanoparticles for actively targeted drug delivery was initially carried out by Farokhzad and Langer et al. in 2004 [118]. As a model drug, the authors created poly (lactic acid)-block-polyethylene glycol copolymer nanoparticles with a terminal carboxylic acid functional group (PLA-b-PEG-COOH). After encasing the nanoparticles in rhodamine-labeled dextran, the authors covalently attached the PSMA-targeting A10 RNA aptamer to the nanoparticles.

Zhen et al. created an aptamer-functionalized-liposome-CRISPR/Cas9 against Polo-like kinase 1 in prostate tumour cells using a post insertion method [119]. Similar to this, Liang et al. chose an aptamer that was unique to osteosarcoma cells and attached it to PEG-PEI-Cholesterol (PPC) lipopolymer that contained plasmids coding for CRISPR/Cas9 and VEGFA gRNA sequences [120]. They demonstrated cell-specific gene editing and tumour reduction. Dendrimers, chitosan, proteins/peptides, or hybrids are examples of other organic nanomaterials that have been applied. Numerous inorganic nanomaterials have also been investigated in this field, including calcium carbonate, zinc oxide, iron, graphene-based materials, gold (Au) compounds, silver (Ag), mesoporous silica, and others. Magnetic nanomaterials, quantum dot-based nanoparticles, and other unique inorganic nanomaterials are examples. Hybrids of organic and inorganic compounds that have been summarised have also been used. Table 7 provides a categorised list of these nanoparticles and nanomaterials together with information on their payloads, targets, associated tumours, etc. [121].

Table 6: Summary of aptamers used in nano-carriers for the treatment of malignant tumour

Nanomaterials

Drug

 Aptamer Target cell lines Cancer type Therapy method Imaging Reference
Exosomes Doxorubicin sgc8 Ramos cells and CEM cells Lymphoblast Chemotherapy Fluorescence [158]
Organic
CA-PLGA-b-TPGS NPs Docetaxel AS1411 MCF-7 Breast cancer Chemotherapy Fluorescence [145]
Ru(bpy)32+-SiO2 NPs miRNA-21 AS1411 MCF-7 Breast cancer Chemotherapy Fluorescence [148]

Poly (ethylene glycol)-

poly (caprolactone) NPs

 Docetaxel AS1411 GMT8 U87 cells Drain glioblastoma Chemotherapy Fluorescence [20]

Poly (ethylene glycol)-

poly (caprolactone) NPs

 Docetaxel AS1411 C6 cells Brain glioma Chemotherapy Fluorescence [21]
Inorganic
CdTe/CdS quantum dots Doxorubicin MUC1 MCF-7 Breast cancer Chemotherapy Fluorescence [157]
Silver (Ag) nanocluster miR-34a MUC1 MCF-7 Breast cancer - Fluorescence [158]
Gold (Au) - AS1411 A375 Skin cancer

Photothermal

therapy (PTT)

 Fluorescence [153]
Mesoporous SiO2 NPs Doxorubicin MUC1

MDA-MB-231

Cells

 Breast cancer Chemotherapy SPECT [161]
Fe3O4 Doxorubicin PSMA LNCaP cells Prostate-cancer Chemotherapy MRI [161]
Au@ c-Fe2O3 NPs -

MUC-

1aptamer

L929

CHO HT-29

 Colon cancer PTT MRI [166]

Fe3O4–Au

Nanocomposite

 Epirubicin MUC-1 aptamer

MCF-7 and

HT-29

 Breast and colorectal cancer Chemotherapy

Fluorescent

imaging

 [163]
Fe3O4@carbon Doxorubicin

sgc8c

aptamers

 A549 Lung cancer Chemo–PTT MRI imaging [164]

Fe3O4 co-loaded

(PEG-PLGA) NPs

 Doxorubicin AS1411 C26 cells Colon carcinoma cancer Chemotherapy MRI [165]
Au@Ag/–S6 Aptamer S6 aptamer A549 Lung cancer PTT Fluorescence [160]
Au nanocage/SiO2 AS1411 MCF-7 Breast cancer PTT SERS imaging [161]

Table 7: Aptamer-mediated functionalized nanoparticles classified by nanomaterials and payloads

Type of nanoparticles

 Payloads Aptamers Targets Cancers Reference

Lipid based

Nanoparticles

 Liposomes Curcumin, Doxorubicin, Cabazitaxel, Cisplatin, CRISPR-Cas9 plasmid, Docetaxel, Doxorubicin, Paclitaxel, and PLK1 siRNA, TSP

A10, A15, AS1411,

HER3-Ap, PSMA-Ap, TLS1c

 CD133, HER3, MEAR cells, Nucleolin, PSMA, PDGFR Breast cancer, DOX-resistant breast cancer, Hepatoma, lung cancer, prostate cancer [162, 131, 164-170]
PEGylated-liposome

5-FU, Doxorubicin,

Anti-BRAF siRNA

 5TR1, AS1411, M49, Syl3c, TSA14,

CD200R1, EpCAM,

Mucin1, Nucleolin,

TUBO cells

 Basal cell carcinoma, breast cancer, colon carcinoma, melanoma [170, 172, 175, 177-178]
Cationic liposome miR-139–5p EpCAM-Ap EpCAM EpCAM Colorectal Cancer [179]
DOTAP: DOPE liposome Doxorubicin SRZ1 Breast cancer 4T1 cells Breast cancer [180]

Hydrogel

based

nanoparticles

 MCS nanogel Doxorubicin LNCaP-Ap LNCaP cell Prostate cancer [181]
RNA Hydrogel siRNA and miRNA LXL MDA-MB-231cell Triple-negative breast cancer [182]
DNA Hydrogel CpG ONT and Doxorubicin MUC1-Ap MUC1 Breast cancer [183]
Chitosan based nanoparticles Chitosan SN38 MUC1-Ap MUC1 Colon cancer [184]
Chitosan and HA SN38 MUC1-Ap MUC1 Colorectal adenocarcinoma [179]
HAS-CS Paclitaxel MUC1-Ap MUC1 Breast cancer [188]

Dendrimer

based

nanoparticles

PEG-PAMAM

dendrimer Nucleolin

 5-fluorouracil, Camptothecin AS1411 Nucleolin Colorectal cancer, Gastric cancer [191]
DGL-PEG Doxorubicin, ATP-aptamer AS1411, Cyt c-Ap Nucleolin, Cyt c Cervical cancer [189]
ONT-PAMAM dendrimer Doxorubicin A9 PSMA Prostate cancer [194]
Dendrimer MicroRNA S6, sgc8c A549 cell, CCRF-CEM ALL, NSCLC [193]

Alkyl PAMAM

dendrimer Bcl-xL shRNA AS1411 Nucleolin Lung cancer

 Bcl-xL shRNA AS1411 Nucleolin Lung cancer [195]

Polymer based

nanoparticles

 PF127-_-CD-PEG-PLA Doxorubicin AS1411 Nucleolin Breast cancer [196]
pPEGMA-PCL-pPEGMA Doxorubicin AS1411 Nucleolin Pancreatic carcinoma [197]
PLL-alkyl-PEI shRNA AS1411 Nucleolin Lung cancer [198]
PEI EpCAM-siRNA EpCAM-Ap EpCAM Breast cancer, retinoblastoma [199]
PLA-PEG Rhodamine-labeled dextran A10 PSMA Prostate cancer [201]
PCL-MMA/MPEG-MASI Doxorubicin EpCAM-Ap EpCAM Colorectal cancer [200]
PLGA Docetaxel, Paclitaxel, Nutlin-3a, Salinomycin, Triplex forming oligonucleotide, Propranolol A10, A15, AS1411, L5, S2.2, EpCAM-Ap PSMA, CD133, EGFR, MUC1, Nucleolin, TAG-72 Breast cancer, hepatocellular carcinoma, hemangioma, human glial cancer, prostate cancer [20,42,191,203,204]
H40-PLA-PEG Doxorubicin A10 PSMA Prostate cancer [202]
PLGA-PEG

Cisplatin, Docetaxel,

Doxorubicin, Gemcitabine,

Paclitaxel, Salinomycin, Vinorelbine, PI3K-mTOR

inhibitor, anti-miR-21, and cisplatin,

 A10, A15, AS1411, C2NP, EpCAM-Ap, Gint4. T, PSMA-Ap, S1.5, Wy5a CD30, CD133, EpCAM, HPA, Nucleolin, PC-3 cell, PGFR_, PSMA Breast cancer, glioblastoma, glioma, large cell lymphoma, lung cancer, NSCLC, osteosarcoma, cisplatin-resistant ovarian cancer, prostate cancer, TNBC [72,194,206,182]
PF127-β-CD-PEG-PLA Doxorubicin AS1411 Nucleolin Breast cancer [200]
PEI EpCAM-siRNA EpCAM-siRNA EpCAM-Ap EpCAM Breast cancer retinoblastoma [203]
PEG-PCL Docetaxel AS1411, GMT8, S15

Nucleolin, NSCLC,

U87 cells

Glioblastoma, glioma,

lung cancer

 [210, 211, 214]
HPAEG Doxorubicin AS1411 Nucleolin Breast cancer [212]
PβAE and PLGA Epirubicin and antimir-21 5TR1 MUC1 Breast cancer MUC1 Breast cancer [200]
PBABT Docetaxel HER2-Ap HER2 Ovarian cancer [202]
PLGA, PVP Doxorubicin AS1411 Nucleolin Lung cancer [209]
M-PLGA–TPGS Docetaxel AS1411 Nucleolin Cervical cancer [218]

Protein/peptide

based

nanoparticles

 Protamine (HSA) Doxorubicin, ALK-siRNA CD30-Ap CD30 Lymphoma [219]
Elastin-like polypeptide Paclitaxel S2.2 MUC1 Breast cancer [221]
Albumin

Cisplatin, Curcumin,

Doxorubicin

 AS1411, EGFR-Ap, HB5 EGFR, HER2, nucleolin Breast cancer, cervical cancer [147, 85, 240]
Human IgG Genistein, miRNA-29b MUC1-Ap MUC1 NSCLC [222, 223

Nucleic acid

based

nanoparticles

Lipidated GC-rich

DNA hairpin

Doxorubicin and

2’,6’,-dimethyl-azobenzene

 trCLN3 cMet cMet-expressing lung cancer [224]
Aptamer DNA Antisense ONT against P-gp sgc8c CCRF-CEM cell ALL [212]
DNA dendrimer Epirubicin MUC1-Ap, AS1411-Ap MUC1, AS1411 Breast and colon cancers [225]
DNA nanotube Doxorubicin C2NP CD30 Human anaplastic large CD30 cell lymphoma [241]
DNA icosahedra Doxorubicin MUC1-Ap] MUC1 Breast cancer [26]
DNA nanotrain

AKT inhibitor, DAU, DOX,

DNR, EPI, Gold

AS1411, LZH5B,

Sgc8, TA6

CD44, HepG2 cell,

nucleolin, PTK7

 ALL, Breast cancer stem cell, cervical cancer, liver cancer [227, 228, 188, 192]
3WJ-RNA Doxorubicin Endo28 Annexin A2 Ovarian cancer [229]
DNA Holliday junction Doxorubicin AS1411 Nucleolin Colon cancer [220]
DNA

ALK-siRNA, Doxorubicin,

Paclitaxel

CD30-Ap, Gint4. T,

GMT8, Sgc4f, Sgc8, TC01

Cancer cells, CD30,

PDGFR_, PTK7,

U87MG cell

 ALCL, ALL, Glioblastoma [231, 238]
DNA nano-ring Doxorubicin MUC1-Ap MUC1 Breast cancer [232]
DNA origami Antisense ONT, doxorubicin MUC1-Ap MUC1 MDR cervical cancer MUC1 MDR cervical cancer [187]

Nucleic acid

and peptide

hybrids

 PAM (peptide +DNA ON) Peptide C10.36 HBLL B-cell leukemia [236]
KLA-DNA micelle Doxorubicin+KLA MUC1-Ap MUC1 Breast cancer [132]
ssDNA-ELP Docetaxel MUC1-Ap MUC1 Breast cancer [216]

Chitosan and

lipid hybrids

 Chitosan-liposome Erlotinib EGFR-Ap EGFR EGFR-mutated cancer cells [213]
Chitosan-liposome PFOB and Erlotinib EGFR-Ap EGFR NSCLC [238]

Polymer and

chitosan

hybrids

 PLGA-chitosan Epirubicin 5TR1 MUC1 Breast cancer, colon carcinoma [110]
Chitosan-ss-PEEUA TLR4-siRNA, AS1411 Nucleolin AS1411 Nucleolin Lung cancer [240]

Polymer and

lipid hybrids

 Polymer-lipid

All-trans retinoic acid,

Curcumin and Cabazitaxel,

Salinomycin

 A10–3.2, A15, CD20-Ap, CD133-Ap, CL4, EGFR-Ap

CD20, CD133, EGFR,

PSMA

Melanoma, osteosarcoma,

prostate cancer

 [216]
PLGA-lecithin-PEG Paclitaxel, Curcumin AS1411, EpCAM Nucleolin

Breast cancer, colorectal

adenocarcinoma

 [52]

DOTAP, PLGA,

cholesterol, Mal-PEG

 P-gp siRNA A6 HER2 DOX-resistant breast cancer [241]
Lipid-PLGA All-trans retinoic acid CD133-Ap CD133 Lung cancer [150]
PLGA-lipid-PEG Docetaxel XEO2 mini PC3 cells Prostate cancer [243]
Lipid-polymer liposome siRNA A6 HER2 Breast cancer [244]

Quantum dot

based

nanoparticles

 QD-PMAT-PEI PSMA siRNA PSMA-Ap PSMA Prostate cancer [18]
Quantum dots None S15 NSCLC Lung cancer [159]
Lipid-quantum dot siRNA EGFR-Ap EGFR Triple-negative breast cancer [145]

Other organic

Nanoparticles

 PEG-aptamer micelle Aptamer FKN-S2 Fractalkine Colon adeno-carcinoma [123]
Atelocollagen MicroRNA A10–3.2 PSMA Prostate cancer [58]
Diacetylene-PEG None ACE4 Annexin A2 Breast cancer [56]
Ursolic acid Doxorubicin HER2-Ap HER2 HER2-carrying cells [125]
Tocopheryl PEG-PβAE Docetaxel AS1411 Nucleolin Ovarian cancer [75]
TD-PEC-chitosan miR-145 AS1411 Nucleolin Breast cancer [139]
LP-DNA SATB1 siRNA EGFR-Ap EGFR Choriocarcinoma [151]

Inorganic

Nanoparticles

 Silver-PEG Irradiation AS1411 Nucleolin Glioma [246]
ZnO Doxorubicin S2.2 MUC1 Breast cancer [90]
Gold Anti-miR-155, Antisense ONT, Daunorubicin, Doxorubicin, TMPyP4, PTT A9, AIR-3A, AS1411, As42, CD30-Ap, CD33/CD34-Ap, KW16–13, UC1-Ap, sgc8c, U2

CCRF-CEM, CD30,

CD33/CD34, EGFR,

Ehrlich’s ACC, IL-6R, MCF10CA1h, MUC1, nucleolin, PSMA

 ALL, AML, breast cancer, cervical cancer, Ehrlich carcinoma, glioblastoma, human breast duct carcinoma, lymphoma, lung cancer, prostate cancer [245, 129, 87]

Other

inorganic

nanoparticles

 Gd: SrHap Doxorubicin AS1411 Nucleolin Breast cancer [236]

Organic and

inorganic

hybrids

 BSA-PEG-Fe3+ Mn, Doxorubicin Glut-1-Ap Glut-1 Liver cancer [131]
MOF-UCNP Doxorubicin AS1411 Nucleolin Breast cancer [213]
Aminopropyl MSN Safranin O MUC1-Ap MUC1 Breast cancer [246]
PDA/PEG-coated MSN DM1 EpCAM-Ap EpCAM Colorectal cancer [221]
Gold-liposome Docetaxel, Morin AS1411, S2.2 Nucleolin, MUC1 Breast cancer, gastric cancer [247, 239]
Albumin-IONP/GNP Doxorubicin AS1411 Nucleolin Breast cancer [133]
CaCO3 and protamine CRISPR-Cas9 plasmid AS1411 Nucleolin NSCLC [248]
NMOF Doxorubicin AS1411, VEGF-Ap Nucleolin, VEGF Breast cancer [249]
β-CD-capped MSN Doxorubicin HApt HER2 HER2-positive cells [133]
TiO2 nanofiber with BSA None AS1411 Nucleolin Breast cancer CTCs [206]
PEG-Au-PAMAM Curcumin MUC1-Ap MUC1 Colon adenocarcinoma [191]
MPC-PAA/PEI Doxorubicin MUC1-Ap MUC1 Breast cancer, lung cancer [221]
Aminopropyl MSN Safranin O MUC1-Ap MUC1 Breast cancer [160]
Others type Ag-MOF-RBCm Doxorubicin CD20-Ap CD20 B-cell lymphoma [250]
Micro-emulsion Shikonin and docetaxel AS1411 and HA Nucleolin and CD44 Glioma [180]

Upconversion

nanoparticle

 Protoporphyrin IX AS1411 Nucleolin Cervical cancer, lung cancer [251]
RBC membrane Doxorubicin, siRNA AS1411 Nucleolin MDR breast cancer [252]
FO-loaded MOF-RBCm Using PDT and CDT effects AS1411 Nucleolin KB Cell Line [253]
NIR PLN Afatinib MAGE-A3 MAGE NSCLC [254]
Cationic nanobubble FoxM1 siRNA A10–3.2 PSMA Prostate cancer [74]

For aptamers that do not have a name, “target-Ap” is used to represent the aptamer; for example, EpCAM-Ap represents the aptamer that targets EpCAM.

Future perspectives

Significant challenges that these restorative techniques face are discussed below for clinical interpretation. The limited choice of aptamers for clinical usage is one issue right away. Aptamers are single-stranded, short nucleic acids that have a propensity to debase in a nuclease-containing physiological environment. Meanwhile, in vitro selection was used to create the majority of aptamers in the literature. The likelihood of losing their affinity in the physiological milieu in vivo is high. As a result, novel SELEX procedures and aptamer stabilisation techniques are urgently required. Additionally, nothing is known about the in vivo pharmacokinetics, pharmacodynamics, and off-target consequences of aptamer-conjugated medicinal compounds.

Aptamer-functionalized systems are likely to acquire novel properties in size, structure, and surface charge compared to conventional materials-based nanomedicines. These traits could affect cellular uptake, biodistribution, metabolism, and excretion in vivo. Only a small number of studies have, to date, evaluated these therapeutic systems in vivo, and different experimental paradigms for the same nanocarriers have produced inconsistent results [122]. As a result, trustworthy and uniform animal models ought to be developed to enable systematic and widespread in vivo assessments of treatment candidates with aptamers attached [123].

Prior to conducting clinical trials, the biosafety issue around aptamer-based nanomedicines needs to be resolved. As aptamers for foreign nucleic acids may carry some hazards of genome insertion, it is important to comprehend immunological reactions. Additionally, some materials that have been functionalized by aptamers have cytotoxicity built right in. Systematic toxicity analyses of potential aptamers-integrated therapeutics must be carried out to guarantee biosafety for clinical trials, whereas artificial intelligence (AI), which includes machine deep-learning techniques, may be a useful tool for overcoming the aforementioned issues in the near future [124, 125]. Whatever the challenges, efforts are being undertaken to solve many of these problems. For example, researchers developed a number of material change and circularization techniques for aptamers that are susceptible to nuclease corruption in order to improve their serum strength, some of which essentially stabilised aptamers for lengthy in vivo research. With in vivo advancement techniques, progress has also been made in identifying potent aptamers.

Inferences of aptamers in clinical trials

Pegaptanib, which has been used to treat age-related macular degeneration, is the first commercial and therapeutic example of the usage of aptamers [126]. Antagonising vascular endothelial growth factor is what this aptamer does. Clinical models, however, have demonstrated that this aptamer has no significant impact on oncology applications. However, effective aptamers have been created for the treatment of cancer, such as NOXA12 and AS1411, which target nucleolin and have good clinical activity [262]. Due to its excellent nuclear resistance, the NOX-A12 aptamer with L-form also has a good half-life after 4 to 6 mo of treatment [128, 129]. The aptamer NOX-A12's clinical activity in the treatment of hematologic malignancies demonstrates that it not only decreased the receptivity of multiple myeloma cells to the bone marrow niche microenvironment but also successfully prevented their chemotaxis towards CXCL12 and decreased drug resistance by mediating cancer cell adhesion [130]. The effectiveness of this aptamer in combination with pembrolizumab for the treatment of metastatic colorectal and pancreatic cancer is still being investigated. Table 9 includes a summary of clinical activities involving aptamers that have been approved.

Table 9: Advance aptamers in clinical and preclinical trials

S. No. Aptamer

Nucleotide

 Target Disease Reference
BT200 RNA vWF, Factor VIII von Willebrand disease Hemophilia A [263]
NU172 DNA Thrombin Heart [261]
EYE001 RNA VEGF Macular degeneration [261]
Zimura RNA Anti-c5 Age-Related Macular (pre-clinical [256]
Pegnivacogen RNA with 50 -PEG and 30 inverted dT Coronary artery disease Phase III completed Regado Biosciences Phase III completed Regado Biosciences [258]
68Ga-Sgc8 DNA PTK7 (CCK4) Colorectal cancer [264]
ARC1779 DNA vWF Thrombotic thrombocytopenic purpura [260]
REG1 RNA Coagulation Factor IX Coronary Artery [263]
NOX-E36 RNA CCL2 Type 2 Diabetes mellitus [257, 262]
AS1411 DNA Nucleolin Acute myeloid leukemia (AML) Nucleolin Acute myeloid leukemia (AML) [262]
E10030 DNA PDGF PDGF Age-Related Macular [258, 259]

CONCLUSION

Despite some gaps in their development for clinical applications, aptamers will be widely used in virus detection and therapy in the near future thanks to the development of new tools and the fusion of high-throughput sequencing with high-throughput binding analysis. Aptamers with high affinity and specificity for clinical use will also become more and more accessible and quick. A good targeting ligand for targeted therapy is an aptamer because of its high affinity and specificity. Different aptamer-based drug delivery techniques have been created, such as aptamer-chemotherapy agents, aptamer-siRNA/shRNA/miRNA, aptamer-antibody, aptamer-enzyme, and aptamer-nanoparticles, to deliver the drug precisely to the expected sites, reducing the risk of side effects brought on by the off-target effects.

ABBREVIATIONS

PDGFR platelet-derived growth factor receptor, PEC polyelectrolyte complexe, PEEUA polyethylenimine-urocanic acid, PEG polyethylene glycol, PEI polyethylene imine, PF127 Pluronic F127, PFK15 1-(4-pyridyl)-3-(2-quinoline)-2-propyl-1-one (an aerobic glycolysis inhibitor), PFOB Perfluorooctylbromide, PGFR-platelet-derived growth factor receptor, P-gp P-glycoprotein, PLA poly (lactic acid), PLGA poly (lactic-co-glycolic acid), PLK1 Polo-Like Kinase 1, PLL poly (L-lysine), pPEGMA-PCL-pPEGMA poly(poly(ethylene glycol) methacrylate)-poly(caprolactone)-poly(poly(ethylene glycol) methacrylate), PTK7 protein tyrosine kinase-7, PTT Photothermal therapy, PVP poly (N-vinylpyrrolidone), QD quantum dot, RBCm red blood cell membrane, SATB1 special AT-rich sequence binding protein 1, SPION superparamagnetic iron oxide nanoparticles, SPMFN Superparamagnetic Ferroarabinogalactan Nanoparticles, TAG-72 tumor-associated glycoprotein 72, TD thiolated dextran, TiO2 titanium dioxide, TLR Toll-like receptor TLR4-siRNA, TM-JM1/2 transmembrane-juxtamembrane 1/2 domain, TMPyP 5, 10, 15, 20-tetra (phenyl-4-N-methyl-4-pyridyl) porphyrin, TMPyP4 5,10,15,20-tetrakis(1-methylpyridinium-4-yl) porphyrin, TNBC triple-negative breast cancer, TPGS D-_-tocopheryl polyethylene glycol 1000 succinate, TSP thermosensitive polymer, UCNP up-conversion luminescent, NaYF4 Yb (3+)/Er (3+) nanoparticle, VEGF vascular endothelial growth factor, β-CD-cyclodextrin, 3WJ-RNA a highly stable three-way junction (3WJ) motif from phi29 packaging RNA, 5-FU 5-fluorouracil, ALCL anaplastic large cell lymphoma, ALK anaplastic lymphoma kinase, ALL acute lymphoblastic leukemia, also known as T-cell acute lymphoblastic leukemia, AML-M2 acute myeloid leukemia subtype 2, APTES (3-aminopropyl) triethoxysilane, BSA bovine serum albumin, cMet hepatocyte growth factor receptor, COOH (terminal) carboxylic acid group, CSC cancer stem cell, CTC circulating tumor cell, CUR-NP curcumin-loaded lipid-polymer-lecithin hybrid nanoparticle, Cyt c cytochrome c, DAU daunorubicin, DGL dendrigraftpoly-L-lysines, DOTAP 1,2-dioleoyl-3-trimethylammonium-propane, dsDNA double-stranded DNA, DSPE 1,2-distearoyl-sn-glycero-3-phosphoethanolamine, EGFR Epidermal growth factor receptor, EHH electrostatic adsorption, hydrogen bonding, and hydrophobic interaction, Ehrlich’s ACC Ehrlich’s ascites carcinoma cell, ELP elastin-like polypeptide, EpCAM epithelial cell adhesion molecule, FGFR1 fibroblast growth factor receptor type-1, FMSN fluorescent mesoporous silica nanoparticle, FN fibronectin, FO Ferric oxide, FoxM1 Forkhead box M1, Gd: SrHap gadolinium-doped luminescent and mesoporous strontium hydroxyapatite, GMNP gold-coated magnetic nanoparticle, GNP gold nanoparticle, GO Graphene oxide, GPN gefitinib-loaded poly (lactic co-glycolic acid) nanoparticle, GQD graphene quantum dot, GST glutathione S-transferase, HA Hyaluronic acid, HAS-CS human serum albumin coated with chitosan, HBLL human B cell leukemia and lymphoma, HCC Hepatocellular carcinoma, HER3 human epidermal growth factor receptor 3, His hexahistidine, HMME is a photosensitizer, HPA heparinase, HPAEG poly(2-((2-(acryloyloxy)ethyl)disulfanyl)ethyl4-cyano-4-(((propylthio)carbonothioyl)-thio)-pentanoate-co-poly(ethylene glycol) methacrylate), HSP71 heat shock cognate 71 kDa protein, HTT hyperthermia therapy, IL-6R interleukin-6 receptor, IONP Iron oxide nanoparticle, KG6E glutamic acid-modified dendritic poly(L-lysine) system, KLA (KLAKLAK)2 peptide, LP-DNA liposome-polycation-DNA, MAA methacrylamide, MAGE melanoma-associated peptide antigen, MAL maleimide, MASI N-(methacryloxy)succinimide, MCS Myristylated Chitosan, MMA methyl methacrylate, MOF (mesoporous) metal-organic framework, MPC mesoporous carbon, MPEG Poly(ethylene glycol) methyl ether, M-PLGA mannitol-functionalized poly(lactide-co-glycolide), MSN Mesoporous silica nanoparticle, mTEC mouse tumor endothelial cell, MDR multiple drug resistance, ONT oligonucleotide, PAA polyacrylic acid, PAM Peptide amphiphile micelle, PAMAM polyamidoamine, PBABT poly (butylene adipate-co-butylene terephthalate), PCL poly (ε-capro-lactone), MUC1 Mucin-1, NHS N-hydroxysuccinimide, NIR PLN near infrared-persistent luminescence nanomaterials, NMOF amino-triphenyl dicarboxylate-bridged Zr4+metal-organic framework nanoparticle, NSCLC non-small cell lung cancer.

FUNDING

Nil

AUTHORS CONTRIBUTIONS

All authors are contributed equally.

CONFLICTS OF INTERESTS

The authors declare no conflict of interest.

REFERENCES

  1. Alshaer W, Hillaireau H, Fattal EJA. Aptamer-guided nanomedicines for anticancer drug delivery. Adv Drug Deliv Rev. 2018 Sep;134:122-37. doi: 10.1016/j.addr.2018.09.011, PMID 30267743.

  2. Guan B, Zhang X. Aptamers as versatile ligands for biomedical and pharmaceutical applications. Int J Nanomedicine. 2020;15:1059-71. doi: 10.2147/IJN.S237544, PMID 32110008.

  3. Han J, Gao L, Wang J, Wang J. Application and development of aptamer in cancer: from clinical diagnosis to cancer therapy. J Cancer. 2020 Oct;11(23):6902-15. doi: 10.7150/jca.49532, PMID 33123281.

  4. Shi J, Kantoff PW, Wooster R, Farokhzad OC. Cancer nanomedicine: progress, challenges and opportunities. Nat Rev Cancer. 2017 Jan;17(1):20-37. doi: 10.1038/nrc.2016.108, PMID 27834398.

  5. Quader S, Kataoka K. Nanomaterial enabled cancer therapy. Mol Ther. 2017 Jul;25(7):1501-13. doi: 10.1016/j.ymthe.2017.04.026, PMID 28532763.

  6. Wang T, Chen C, Larcher LM, Barrero RA, Veedu RN. Three decades of nucleic acid aptamer technologies: lessons learned, progress and opportunities on aptamer development. Biotechnol Adv. 2019 Feb;37(1):28-50. doi: 10.1016/j.biotechadv.2018.11.001, PMID 30408510.

  7. Gold L, Janjic N, Jarvis T, Schneider D, Walker JJ, Wilcox SK. Aptamers and the RNA world, past and present. Cold Spring Harb Perspect Biol. 2012 Mar;4(3):1-9. doi: 10.1101/cshperspect.a003582, PMID 21441582.

  8. Ni X, Castanares M, Mukherjee A, Lupold SE. Nucleic acid aptamers: clinical applications and promising new horizons. Curr Med Chem. 2011;18(27):4206-14. doi: 10.2174/092986711797189600, PMID 21838685.

  9. Röthlisberger P, Hollenstein M. Aptamer chemistry. Adv Drug Deliv Rev. 2018 Sep;134:3-21. doi: 10.1016/j.addr.2018.04.007, PMID 29626546.

  10. Yoo H, Jo H, Oh SS. Detection and beyond: challenges and advances in aptamer-based biosensors. Mater Adv. 2020 Oct;1(8):2663-87. doi: 10.1039/D0MA00639D.

  11. Song Y, Song J, Wei X, Huang M, Sun M, Zhu L. Discovery of aptamers targeting the receptor-binding domain of the SARS-CoV-2 spike glycoprotein. Anal Chem. 2020;92(14):9895-900. doi: 10.1021/acs.analchem.0c01394, PMID 32551560.

  12. Kruger A, de Jesus Santos AP, de Sa V, Ulrich H, Wrenger C. Aptamer applications in emerging viral diseases. Pharmaceuticals (Basel). 2021 Jun;14(7):1-19. doi: 10.3390/ph14070622, PMID 34203242.

  13. Barman J. Targeting cancer cells using aptamers: cell-SELEX approach and recent advancements. RSC Adv. 2015 Jan;5(16):11724-32. doi: 10.1039/C4RA12407C.

  14. Vinores SA. Pegaptanib in the treatment of wet, age-related macular degeneration. Int J Nanomedicine. 2006 Sep;1(3):263-8. PMID 17717967.

  15. Lao YH, Phua KKL, Leong KW. Aptamer nanomedicine for cancer therapeutics: barriers and potential for translation. ACS Nano. 2015 Mar;9(3):2235-54. doi: 10.1021/nn507494p, PMID 25731717.

  16. Maier KE, Levy M. From selection hits to clinical leads: progress in aptamer discovery. Mol Ther Methods Clin Dev. 2016 Apr;5:16014. doi: 10.1038/mtm.2016.14, PMID 27088106.

  17. Mallikaratchy P. Evolution of complex target SELEX to identify aptamers against mammalian cell-surface antigens. Molecules. 2017 Jan;22(2):215. doi: 10.3390/molecules22020215, PMID 28146093.

  18. Engelberg S, Modrejewski J, Walter JG, Livney YD, Assaraf YG. Cancer cell-selective, clathrin-mediated endocytosis of aptamer decorated nanoparticles. Oncotarget. 2018 Apr;9(30):20993-1006. doi: 10.18632/oncotarget.24772, PMID 29765515.

  19. Futami K, Kimoto M, Lim YWS, Hirao I. Genetic alphabet expansion provides versatile specificities and activities of unnatural-base DNA aptamers targeting cancer cells. Mol Ther Nucleic Acids. 2019 Mar;14:158-70. doi: 10.1016/j.omtn.2018.11.011, PMID 30594072.

  20. Gao H, Qian J, Cao S, Yang Z, Pang Z, Pan S. Precise glioma targeting of and penetration by aptamer and peptide dual-functioned nanoparticles. Biomaterials. 2012 Jul;33(20):5115-23. doi: 10.1016/j.biomaterials.2012.03.058, PMID 22484043.

  21. Gao H, Qian J, Yang Z, Pang Z, Xi Z, Cao S. Whole-cell SELEX aptamer-functionalised poly(ethyleneglycol)-poly(ε-caprolactone) nanoparticles for enhanced targeted glioblastoma therapy. Biomaterials. 2012 Sep;33(26):6264-72. doi: 10.1016/j.biomaterials.2012.05.020, PMID 22683171.

  22. Zhou J, Rossi J. Aptamers as targeted therapeutics: current potential and challenges. Nat Rev Drug Discov. 2017 Mar;16(3):181-202. doi: 10.1038/nrd.2016.199, PMID 27807347.

  23. Lakhin AV, Tarantul VZ, Gening LV. Aptamers: problems, solutions and prospects. Acta Nat. 2013 Oct;5(4):34-43. doi: 10.32607/20758251-2013-5-4-34-43, PMID 24455181.

  24. Levy Nissenbaum E, Radovic Moreno AF, Wang AZ, Langer R, Farokhzad OC. Nanotechnology and aptamers: applications in drug delivery. Trends Biotechnol. 2008 Jun;26(8):442-9. doi: 10.1016/j.tibtech.2008.04.006, PMID 18571753.

  25. Thiel KW, Giangrande PH. Therapeutic applications of DNA and RNA aptamers. Oligonucleotides. 2009 Sep;19(3):209-22. doi: 10.1089/oli.2009.0199, PMID 19653880.

  26. Huang YF, Sefah K, Bamrungsap S, Chang HT, Tan W. Selective photothermal therapy for mixed cancer cells using aptamer-conjugated nanorods. Langmuir. 2008 Oct 21;24(20):11860-5. doi: 10.1021/la801969c, PMID 18817428.

  27. Wang Q, Liu W, Xing Y, Yang X, Wang K, Jiang R. Screening of DNA aptamers against myoglobin using a positive and negative selection unit integrated microfluidic chip and its biosensing application. Anal Chem. 2014 Jul 1;86(13):6572-9. doi: 10.1021/ac501088q, PMID 24914856.

  28. Mosing RK, Mendonsa SD, Bowser MT. Capillary electrophoresis-SELEX selection of aptamers with affinity for HIV-1 reverse transcriptase. Anal Chem. 2005 Oct;77(19):6107-12. doi: 10.1021/ac050836q, PMID 16194066.

  29. Ahn JY, Jo M, Dua P, Lee DK, Kim S. A sol-gel-based microfluidics system enhances the efficiency of RNA aptamer selection. Oligonucleotides. 2011 Mar;21(2):93-100. doi: 10.1089/oli.2010.0263, PMID 21413890.

  30. Khan S, Hussain A, Fahimi H, Aliakbari F, Haj Bloukh S, Edis Z. A review on the therapeutic applications of aptamers and aptamer-conjugated nanoparticles in cancer, inflammatory and viral diseases. Arab J Chem. 2022;15(2):103626. doi: 10.1016/j.arabjc.2021.103626.

  31. Taghavi Estevez AS, Sahar N, Hashem A, Khalil A, Ramezani M. Polyethylenimine-functionalized carbon nanotubes tagged with AS1411 aptamer for combination gene and drug delivery into human gastric cancer cells. Letter to the editor. Int J Pharm. 2016 Jan;497(1):2-42.

  32. Zhang Y, Lai BS, Juhas M. Recent advances in aptamer discovery and applications. Molecules. 2019 Jan;24(5):941. doi: 10.3390/molecules24050941, PMID 30866536.

  33. Mercier MC, Dontenwill M, Choulier L. Selection of nucleic acid aptamers targeting tumor cell-surface protein biomarkers. Cancers (Basel). 2017 Jun;9(6):69. doi: 10.3390/cancers9060069, PMID 28635657.

  34. Yang C, Jiang Y, Hao SH, Yan XY, Hong F, Naranmandura H. Aptamers: an emerging navigation tool of therapeutic agents for targeted cancer therapy. J Mater Chem B. 2021 Dec 22;10(1):20-33. doi: 10.1039/d1tb02098f, PMID 34881767.

  35. Stoltenburg R, Nikolaus N, Strehlitz B. Capture-SELEX: selection of DNA aptamers for aminoglycoside antibiotics. J Anal Methods Chem. 2012;2012:415697. doi: 10.1155/2012/415697, PMID 23326761.

  36. Lauridsen LH, Doessing HB, Long KS, Nielsen AT. A capture-SELEX strategy for multiplexed selection of RNA aptamers against small molecules, Synth. Metab Pathw. 2018;(1671):291-306.

  37. Yang J, Bowser MT. Capillary electrophoresis-SELEX selection of catalytic DNA Aptamers for a small-molecule porphyrin target. Anal Chem. 2013 Feb;85(3):1525-30. doi: 10.1021/ac302721j, PMID 23234289.

  38. Hamedani NS, Müller J. Capillary electrophoresis for the selection of DNA aptamers recognizing activated protein C. Methods Mol Biol. 2016;1380:61-75. doi: 10.1007/978-1-4939-3197-2_5, PMID 26552816.

  39. Takenaka M, Okumura Y, Amino T, Miyachi Y, Ogino C, Kondo A. DNA-duplex linker for AFM-SELEX of DNA aptamer against human serum albumin. Bioorg Med Chem Lett. 2017;27(4):954-7. doi: 10.1016/j.bmcl.2016.12.080, PMID 28094182.

  40. Miyachi Y, Shimizu N, Ogino C, Kondo A. Selection of DNA aptamers using atomic force microscopy. Nucleic Acids Res. 2010 Mar;38(4):e21. doi: 10.1093/nar/gkp1101, PMID 19955232.

  41. Ahn JY, Lee S, Jo M, Kang J, Kim E, Jeong OC. Sol-gel derived nanoporous compositions for entrapping small molecules and their outlook toward aptamer screening. Anal Chem. 2012 Mar;84(6):2647-53. doi: 10.1021/ac202559w, PMID 22283623.

  42. Azhdarzadeh M, Atyabi F, Saei AA, Varnamkhasti BS, Omidi Y, Fateh M. Theranostic MUC-1 aptamer targeted gold coated superparamagnetic iron oxide nanoparticles for magnetic resonance imaging and photothermal therapy of colon cancer. Colloids Surf B Biointerfaces. 2016 Jul 1;143:224-32. doi: 10.1016/j.colsurfb.2016.02.058, PMID 27015647.

  43. Mayer G, Ahmed MS, Dolf A, Endl E, Knolle PA, Famulok M. Fluorescence-activated cell sorting for aptamer SELEX with cell mixtures. Nat Protoc. 2010 Dec;5(12):1993-2004. doi: 10.1038/nprot.2010.163, PMID 21127492.

  44. Oh SS, Qian J, Lou X, Zhang Y, Xiao Y, Soh HT. Generation of highly specific aptamers via micromagnetic selection. Anal Chem. 2009 Jul;81(13):5490-5. doi: 10.1021/ac900759k, PMID 19480397.

  45. Tawiah KD, Porciani D, Burke DH. Toward the selection of cell targeting aptamers with extended biological functionalities to facilitate endosomal escape of cargoes. Biomedicines. 2017 Aug 24;5(3):51. doi: 10.3390/biomedicines5030051, PMID 28837119.

  46. Mayer G, Ahmed MS, Dolf A, Endl E, Knolle PA, Famulok M. Fluorescence-activated cell sorting for aptamer SELEX with cell mixtures. Nat Protoc. 2010 Dec;5(12):1993-2004. doi: 10.1038/nprot.2010.163, PMID 21127492.

  47. Tombelli S, Minunni M, Mascini M. Analytical applications of aptamers. Biosens Bioelectron. 2005 Jun;20(12):2424-34. doi: 10.1016/j.bios.2004.11.006, PMID 15854817.

  48. Sun W, Du L, Li M. Advances and perspectives in cell-specific aptamers. Curr Pharm Des. 2011;17(1):80-91. doi: 10.2174/138161211795049769, PMID 21342116.

  49. Haisler WL, Timm DM, Gage JA, Tseng H, Killian TC, Souza GR. Three-dimensional cell culturing by magnetic levitation. Nat Protoc. 2013 Oct;8(10):1940-9. doi: 10.1038/nprot.2013.125, PMID 24030442.

  50. Zumrut HE, Ara MN, Fraile M, Maio G, Mallikaratchy P. Ligand-guided selection of target-specific aptamers: a screening technology for identifying specific aptamers against cell-surface proteins. Nucleic Acid Ther. 2016 Jun;26(3):190-8. doi: 10.1089/nat.2016.0611, PMID 27148897.

  51. Hicke BJ, Marion C, Chang YF, Gould T, Lynott CK, Parma D. Tenascin-C aptamers are generated using tumor cells and purified protein. J Biol Chem. 2001 Dec;276(52):48644-54. doi: 10.1074/jbc.M104651200, PMID 11590140.

  52. Aravind A, Jeyamohan P, Nair R, Veeranarayanan S, Nagaoka Y, Yoshida Y. AS1411 aptamer tagged PLGA-lecithin-PEG nanoparticles for tumor cell targeting and drug delivery. Biotechnol Bioeng. 2012 Nov;109(11):2920-31. doi: 10.1002/bit.24558, PMID 22615073.

  53. Almasi F, Mousavi Gargari SL, Bitaraf F, Rasoulinejad S. Development of a single stranded DNA aptamer as a molecular probe for lncap cells using CELL-SELEX. Avicenna J Med Biotechnol. 2016 Jul;8(3):104-11, PMID 27563422.

  54. Wang L, Wang R, Chen F, Jiang T, Wang H, Slavik M. Qcm-based aptamer selection and detection of salmonella typhimurium. Food Chem. 2017 Apr;221:776-82. doi: 10.1016/j.foodchem.2016.11.104, PMID 27979272.

  55. Mendonsa SD, Bowser MT. In vitro evolution of functional DNA using capillary electrophoresis. J Am Chem Soc. 2004 Jan;126(1):20-1. doi: 10.1021/ja037832s, PMID 14709039.

  56. Doerflinger A, Quang NN, Gravel E, Duconge F, Doris E. Aptamer-decorated polydiacetylene micelles with improved targeting of cancer cells. Int J Pharm. 2019 Jun 30;565:59-63. doi: 10.1016/j.ijpharm.2019.04.071, PMID 31029658.

  57. Hamedani NS, Müller J. Capillary electrophoresis for the selection of DNA aptamers recognizing activated protein C. Methods Mol Biol. 2016;1380:61-75. doi: 10.1007/978-1-4939-3197-2_5, PMID 26552816.

  58. Hao Z, Fan W, Hao J, Wu X, Zeng GQ, Zhang LJ. Efficient delivery of micro RNA to bone-metastatic prostate tumors by using aptamer-conjugated atelocollagen in vitro and in vivo. Drug Deliv. 2016;23(3):874-81. doi: 10.3109/10717544.2014.920059, PMID 24892627.

  59. Mi J, Liu Y, Rabbani ZN, Yang Z, Urban JH, Sullenger BA. In vivo selection of tumor-targeting rna motifs. Nat Chem Biol. 2010 Jan;6(1):22-4. doi: 10.1038/nchembio.277, PMID 19946274.

  60. Cheng C, Chen YH, Lennox KA, Behlke MA, Davidson BL. In vivo selex for identification of brain-penetrating aptamers. Mol Ther Nucleic Acids. 2013 Jan;2(1):e67. doi: 10.1038/mtna.2012.59, PMID 23299833.

  61. Cho M, Xiao Y, Nie J, Stewart R, Csordas AT, Oh SS. Quantitative selection of DNA aptamers through microfluidic selection and high-throughput sequencing. Proc Natl Acad Sci USA. 2010 Aug;107(35):15373-8. doi: 10.1073/pnas.1009331107, PMID 20705898.

  62. Berezhnoy A, Stewart CA, McNamara JO, Thiel W, Giangrande P, Trinchieri G. Isolation and optimization of murine IL-10 receptor blocking oligonucleotide aptamers using high-throughput sequencing. Mol Ther. 2012 Jun;20(6):1242-50. doi: 10.1038/mt.2012.18, PMID 22434135.

  63. Scoville DJ, Uhm TK, Shallcross JA, Whelan RJ. Selection of DNA aptamers for ovarian cancer biomarker CA125 using one-pot selex and high-throughput sequencing. J Nucleic Acids. 2017 Feb;2017:9879135. doi: 10.1155/2017/9879135, PMID 28280637.

  64. Thiel WH. Galaxy workflows for web-based bioinformatics analysis of aptamer high-throughput sequencing data. Mol Ther Nucleic Acids. 2016 Aug;5(8):e345. doi: 10.1038/mtna.2016.54, PMID 28131286.

  65. Kanwar JR, Mohan RR, Kanwar RK, Roy K, Bawa R. Applications of aptamers in nanodelivery systems in cancer, eye and inflammatory diseases. Nanomedicine (Lond). 2010 Nov;5(9):1435-45. doi: 10.2217/nnm.10.115, PMID 21128724.

  66. Wan Y, Kim YT, Li N, Cho SK, Bachoo R, Ellington AD. Surface-immobilized aptamers for cancer cell isolation and microscopic cytology. Cancer Res. 2010 Nov 15;70(22):9371-80. doi: 10.1158/0008-5472.CAN-10-0568, PMID 21062984.

  67. Li X, An Y, Jin J, Zhu Z, Hao L, Liu L. Evolution of DNA aptamers through in vitro metastatic-cell-based systematic evolution of ligands by exponential enrichment for metastatic cancer recognition and imaging. Anal Chem. 2015;87(9):4941-8. doi: 10.1021/acs.analchem.5b00637, PMID 25867099.

  68. Takahashi M, Wu X, Ho M, Chomchan P, Rossi JJ, Burnett JC. High throughput sequencing analysis of RNA libraries reveals the influences of initial library and pcr methods on selex efficiency. Sci Rep. 2016 Sep;6:33697. doi: 10.1038/srep33697, PMID 27652575.

  69. Song Y, Zhu Z, An Y, Zhang W, Zhang H, Liu D. Selection of DNA aptamers against epithelial cell adhesion molecule for cancer cell imaging and circulating tumor cell capture. Anal Chem. 2013 Apr 16;85(8):4141-9. doi: 10.1021/ac400366b, PMID 23480100.

  70. Bayrac AT, Sefah K, Parekh P, Bayrac C, Gulbakan B, Oktem HA. In vitro selection of DNA aptamers to glioblastoma multiforme. ACS Chem Neurosci. 2011 Jan 31;2(3):175-81. doi: 10.1021/cn100114k, PMID 21892384.

  71. Boshtam M, Asgary S, Kouhpayeh S, Shariati L, Khanahmad H. Aptamers against pro- and anti-inflammatory cytokines: a review. Inflammation. 2017 Feb;40(1):340-9. doi: 10.1007/s10753-016-0477-1, PMID 27878687.

  72. Ni M, Xiong M, Zhang X, Cai G, Chen H, Zeng Q. Poly(lactic-co-glycolic acid) nanoparticles conjugated with CD133 aptamers for targeted salinomycin delivery to CD133+ osteosarcoma cancer stem cells. Int J Nanomedicine. 2015 Mar 31;10:2537-54. doi: 10.2147/IJN.S78498, PMID 25848270.

  73. Wang Q, Liu W, Xing Y, Yang X, Wang K, Jiang R. Screening of DNA aptamers against myoglobin using a positive and negative selection units integrated microfluidic chip and its biosensing application. Anal Chem. 2014 Jul 1;86(13):6572-9. doi: 10.1021/ac501088q, PMID 24914856.

  74. Wu M, Zhao H, Guo L, Wang Y, Song J, Zhao X. Ultrasound-mediated nanobubble destruction (UMND) facilitates the delivery of A10-3.2 aptamer targeted and siRNA-loaded cationic nanobubbles for therapy of prostate cancer. Drug Deliv. 2018 Nov;25(1):226-40. doi: 10.1080/10717544.2017.1422300, PMID 29313393.

  75. Zhang J, Chen R, Chen F, Chen M, Wang Y. Nucleolin targeting AS1411 aptamer modified pH-sensitive micelles: a dual-functional strategy for paclitaxel delivery. J Control Release. 2015 Sep 10;213:e137-8. doi: 10.1016/j.jconrel.2015.05.232, PMID 27005093.

  76. Xu D, Xu D, Yu X, Liu Z, He W, Ma Z. Label-free electrochemical detection for aptamer-based array electrodes. Anal Chem. 2005 Aug;77(16):5107-13. doi: 10.1021/ac050192m, PMID 16097746.

  77. Wang X, Zhou J, Yun W, Xiao S, Chang Z, He P. Detection of thrombin using electrogenerated chemiluminescence based on Ru(bpy)3(2+)-doped silica nanoparticle aptasensor via target protein-induced strand displacement. Anal Chim Acta. 2007 Aug;598(2):242-8. doi: 10.1016/j.aca.2007.07.050, PMID 17719898.

  78. Cho EJ, Lee JW, Ellington AD. Applications of aptamers as sensors. Annu Rev Anal Chem (Palo Alto Calif). 2009;2:241-64. doi: 10.1146/annurev.anchem.1.031207.112851, PMID 20636061.

  79. Ikebukuro K, Kiyohara C, Sode K. Novel electrochemical sensor system for protein using the aptamers in sandwich manner. Biosens Bioelectron. 2005 Apr;20(10):2168-72. doi: 10.1016/j.bios.2004.09.002, PMID 15741093.

  80. Zou X, Wu J, Gu J, Shen L, Mao L. Application of aptamers in virus detection and antiviral therapy. Front Microbiol. 2019 Jul;10:1462. doi: 10.3389/fmicb.2019.01462, PMID 31333603.

  81. Mor Vaknin N, Saha A, Legendre M, Carmona Rivera C, Amin MA, Rabquer BJ. DEK-targeting DNA aptamers as therapeutics for inflammatory arthritis. Nat Commun. 2017 Feb 6;8:14252. doi: 10.1038/ncomms14252, PMID 28165452.

  82. Zhu G, Chen X. Aptamer-based targeted therapy. Adv Drug Deliv Rev. 2018 Sep;134:65-78. doi: 10.1016/j.addr.2018.08.005, PMID 30125604.

  83. Stojanovic MN, de Prada P, Landry DW. Aptamer-based folding fluorescent sensor for cocaine. J Am Chem Soc. 2001 May;123(21):4928-31. doi: 10.1021/ja0038171, PMID 11457319.

  84. Zhao W, Chiuman W, Brook MA, Li Y. Simple and rapid colorimetric biosensors based on DNA aptamer and noncrosslinking gold nanoparticle aggregation. Chembiochem. 2007 May;8(7):727-31. doi: 10.1002/cbic.200700014, PMID 17410623.

  85. Chen Y, Wang J, Wang J, Wang L, Tan X, Tu K. Aptamer functionalized cisplatin-albumin nanoparticles for targeted delivery to epidermal growth factor receptor-positive cervical cancer. J Biomed Nanotechnol. 2016 Apr;12(4):656-66. doi: 10.1166/jbn.2016.2203, PMID 27301192.

  86. Hianik T, Ostatna V, Zajacova Z, Stoikova E, Evtugyn G. Detection of aptamer-protein interactions using QCM and electrochemical indicator methods. Bioorg Med Chem Lett. 2005 Jan;15(2):291-5. doi: 10.1016/j.bmcl.2004.10.083, PMID 15603942.

  87. Zhang Z, Cheng W, Pan Y, Jia L. An anticancer agent-loaded PLGA nanomedicine with glutathione-response and targeted delivery for the treatment of lung cancer. J Mater Chem B. 2020 Jan;8(4):655-65. doi: 10.1039/c9tb02284h, PMID 31904073.

  88. Kang H, O’Donoghue MB, Liu H, Tan W. A liposome-based nanostructure for aptamer directed delivery. Chem Commun (Camb). 2010 Jan;46(2):249-51. doi: 10.1039/b916911c, PMID 20024341.

  89. Sokoloski JE, Dombrowski SE, Bevilacqua PC. Thermodynamics of ligand binding to a heterogeneous rna population in the malachite green aptamer. Biochemistry. 2012 Jan;51(1):565-72. doi: 10.1021/bi201642p, PMID 22192051.

  90. Tang Y, Hu H, Zhang MG, Song J, Nie L, Wang S. An aptamer-targeting photoresponsive drug delivery system using ”off-on” graphene oxide wrapped mesoporous silica nanoparticles. Nanoscale. 2015 Apr 14;7(14):6304-10. doi: 10.1039/c4nr07493a, PMID 25782595.

  91. Amero P, Esposito CL, Rienzo A, Moscato F, Catuogno S, de Franciscis V. Identification of an interfering ligand aptamer for EphB2/3 receptors. Nucleic Acid Ther. 2016 Apr;26(2):102-10. doi: 10.1089/nat.2015.0580, PMID 26824783.

  92. Polonschii C, David S, Tombelli S, Mascini M, Gheorghiu MA. A Novel, low-cost and easy-to-develop functionalization platform. Case study: aptamer-based detection of thrombin by surface plasmon resonance. Talanta. 2010 Mar;80(5):2157-64. doi: 10.1016/j.talanta.2009.11.023, PMID 20152466.

  93. Quang NN, Miodek A, Cibiel A, Duconge F. Selection of aptamers against whole living cells: from CELL-SELEX to identification of biomarkers. Methods Mol Biol. 2017;1575:253-72. doi: 10.1007/978-1-4939-6857-2_16, PMID 28255886.

  94. Bruno JG, Kiel JL. In vitro selection of DNA aptamers to anthrax spores with electrochemiluminescence detection. Biosens Bioelectron. 1999 May;14(5):457-64. doi: 10.1016/s0956-5663(99)00028-7, PMID 10451913.

  95. Li X, Zhang W, Liu L, Zhu Z, Ouyang G, An Y. In vitro selection of DNA aptamers for metastatic breast cancer cell recognition and tissue imaging. Anal Chem. 2014 Jul 1;86(13):6596-603. doi: 10.1021/ac501205q, PMID 24892693.

  96. Li X, Zhang W, Liu L, Zhu Z, Ouyang G, An Y. In vitro selection of DNA aptamers for metastatic breast cancer cell recognition and tissue imaging. Anal Chem. 2014 Jun;86(13):6596-603. doi: 10.1021/ac501205q, PMID 24892693.

  97. Pultar J, Sauer U, Domnanich P, Preininger C. Aptamer-antibody on-chip sandwich immunoassay for detection of CRP in spiked serum. Biosens Bioelectron. 2009 Mar;24(5):1456-61. doi: 10.1016/j.bios.2008.08.052, PMID 18951012.

  98. Collett JR, Cho EJ, Ellington AD. Production and processing of aptamer microarrays. Methods. 2005 Apr;37(1):4-15. doi: 10.1016/j.ymeth.2005.05.009, PMID 16199170.

  99. Porciani D, Signore G, Marchetti L, Mereghetti P, Nifosì R, Beltram F. Two interconvertible folds modulate the activity of a DNA aptamer against transferrin receptor. Mol Ther Nucleic Acids. 2014 Jan;3(1):e144. doi: 10.1038/mtna.2013.71, PMID 24472870.

  100. Nishikawa F, Funaji K, Fukuda K, Nishikawa S. In vitro selection of RNA aptamers against the HCV NS3 helicase domain. Oligonucleotides. 2004;14(2):114-29. doi: 10.1089/1545457041526335, PMID 15294075.

  101. Li N, Nguyen HH, Byrom M, Ellington AD. Inhibition of cell proliferation by an anti-EGFR aptamer. PLOS ONE. 2011 Jun;6(6):e20299. doi: 10.1371/journal.pone.0020299, PMID 21687663.

  102. Volk DE, Lokesh GLR. Development of phosphorothioate DNA and DNA thioaptamers. Biomedicines. 2017 Jul 13;5(3):41. doi: 10.3390/biomedicines5030041, PMID 28703779.

  103. Deng R, Qu H, Liang L, Zhang J, Zhang B, Huang D. Tracing the therapeutic process of targeted aptamer/drug conjugate on cancer cells by surface-enhanced Raman scattering spectroscopy. Anal Chem. 2017 Mar;89(5):2844-51. doi: 10.1021/acs.analchem.6b03971, PMID 28192929.

  104. Lupold SE, Hicke BJ, Lin Y, Coffey DS. Identification and characterization of nuclease-stabilized RNA molecules that bind human prostate cancer cells via the prostate-specific membrane antigen. Cancer Res. 2002 Jul 15;62(14):4029-33, PMID 12124337.

  105. Maier KE, Jangra RK, Shieh KR, Cureton DK, Xiao H, Snapp EL. A new transferrin receptor aptamer inhibits new world hemorrhagic fever Mammarenavirus entry. Mol Ther Nucleic Acids. 2016 May 24;5:e321. doi: 10.1038/mtna.2016.32, PMID 27219515.

  106. Raddatz MS, Dolf A, Endl E, Knolle P, Famulok M, Mayer G. Enrichment of cell-targeting and population-specific aptamers by fluorescence-activated cell sorting. Angew Chem Int Ed Engl. 2008;47(28):5190-3. doi: 10.1002/anie.200800216, PMID 18512861.

  107. Li N, Nguyen HH, Byrom M, Ellington AD. Inhibition of cell proliferation by an anti-EGFR aptamer. PLOS ONE. 2011;6(6):e20299. doi: 10.1371/journal.pone.0020299, PMID 21687663.

  108. Somasunderam A, Thiviyanathan V, Tanaka T, Li X, Neerathilingam M, Lokesh GL. Combinatorial selection of DNA thioaptamers targeted to the HA binding domain of human CD44. Biochemistry. 2010 Oct 26;49(42):9106-12. doi: 10.1021/bi1009503, PMID 20843027.

  109. Taghavi S, Ramezani M, Alibolandi M, Abnous K, Taghdisi SM. Chitosan-modified PLGA nanoparticles tagged with 5TR1 aptamer for in vivo tumor-targeted drug delivery. Cancer Lett. 2017 Aug 1;400:1-8. doi: 10.1016/j.canlet.2017.04.008, PMID 28412238.

  110. Thiel KW, Hernandez LI, Dassie JP, Thiel WH, Liu X, Stockdale KR. Delivery of chemo-sensitizing siRNAs to HER2+-breast cancer cells using RNA aptamers. Nucleic Acids Res. 2012 Jul;40(13):6319-37. doi: 10.1093/nar/gks294, PMID 22467215.

  111. Raddatz MS, Dolf A, Endl E, Knolle P, Famulok M, Mayer G. Enrichment of cell-targeting and population-specific aptamers by fluorescence-activated cell sorting. Angew Chem Int Ed Engl. 2008;47(28):5190-3. doi: 10.1002/anie.200800216, PMID 18512861.

  112. Wilner SE, Wengerter B, Maier K, de Lourdes Borba Magalhaes M, Del Amo DS, Pai S. An RNA alternative to human transferrin: a new tool for targeting human cells. Mol Ther Nucleic Acids. 2012 May 15;1(5):e21. doi: 10.1038/mtna.2012.14, PMID 23344001.

  113. Chu TC, Twu KY, Ellington AD, Levy M. Aptamer mediated siRNA delivery. Nucleic Acids Res. 2006 Jun;34(10):e73. doi: 10.1093/nar/gkl388, PMID 16740739.

  114. Bates PJ, Laber DA, Miller DM, Thomas SD, Trent JO. Discovery and development of the G-rich oligonucleotide AS1411 as a novel treatment for cancer. Exp Mol Pathol. 2009 Jun;86(3):151-64. doi: 10.1016/j.yexmp.2009.01.004, PMID 19454272.

  115. Soundararajan S, Wang L, Sridharan V, Chen W, Courtenay Luck N, Jones D. Plasma membrane nucleolin is a receptor for the anticancer aptamer AS1411 in MV4-11 leukemia cells. Mol Pharmacol. 2009 Nov;76(5):984-91. doi: 10.1124/mol.109.055947, PMID 19657047.

  116. Iaboni M, Fontanella R, Rienzo A, Capuozzo M, Nuzzo S, Santamaria G. Targeting insulin receptor with a novel internalizing aptamer. Mol Ther Nucleic Acids. 2016 Sep 20;5(9):e365. doi: 10.1038/mtna.2016.73, PMID 27648925.

  117. Zhou J, Li H, Li S, Zaia J, Rossi JJ. Novel dual inhibitory function aptamer-siRNA delivery system for HIV-1 therapy. Mol Ther. 2008 Aug;16(8):1481-9. doi: 10.1038/mt.2008.92, PMID 18461053.

  118. Alshaer W, Hillaireau H, Vergnaud J, Ismail S, Fattal E. Functionalizing liposomes with anti-CD44 aptamer for selective targeting of cancer cells. Bioconjug Chem. 2015 Jul;26(7):1307-13. doi: 10.1021/bc5004313, PMID 25343502.

  119. McNamara JO, Andrechek ER, Wang Y, Viles KD, Rempel RE, Gilboa E. Cell type-specific delivery of siRNAs with aptamer-siRNA chimeras. Nat Biotechnol. 2006 Aug;24(8):1005-15. doi: 10.1038/nbt1223, PMID 16823371.

  120. Ferreira CS, Cheung MC, Missailidis S, Bisland S, Gariepy J. Phototoxic aptamers selectively enter and kill epithelial cancer cells. Nucleic Acids Res. 2009 Dec;37(3):866-76. doi: 10.1093/nar/gkn967, PMID 19103663.

  121. Harris MA, Pearce TR, Pengo T, Kuang H, Forster C, Kokkoli E. Aptamer micelles targeting fractalkine-expressing cancer cells in vitro and in vivo. Nanomedicine. 2018 Jan;14(1):85-96. doi: 10.1016/j.nano.2017.08.020, PMID 28912042.

  122. McNamara JO, Andrechek ER, Wang Y, Viles KD, Rempel RE, Gilboa E. Cell type-specific delivery of siRNAs with aptamer-siRNA chimeras. Nat Biotechnol. 2006 Aug;24(8):1005-15. doi: 10.1038/nbt1223, PMID 16823371.

  123. Jiang K, Han L, Guo Y, Zheng G, Fan L, Shen Z. A carrier-free dual-drug nanodelivery system functionalized with aptamer specific targeting HER2-overexpressing cancer cells. J Mater Chem B. 2017 Dec 14;5(46):9121-9. doi: 10.1039/c7tb02562a, PMID 32264593.

  124. Bagalkot V, Zhang L, Levy Nissenbaum E, Jon S, Kantoff PW, Langer R. Quantum dot-aptamer conjugates for synchronous cancer imaging, therapy, and sensing of drug delivery based on bi-fluorescence resonance energy transfer. Nano Lett. 2007 Oct;7(10):3065-70. doi: 10.1021/nl071546n, PMID 17854227.

  125. Farokhzad OC, Cheng J, Teply BA, Sherifi I, Jon S, Kantoff PW. Targeted nanoparticle-aptamer bioconjugates for cancer. chemotherapy in vivo. Proc Natl Acad Sci USA. 2006 Apr 18;103(16):6315-20. doi: 10.1073/pnas.0601755103.

  126. Wu Y, Sefah K, Liu H, Wang R, Tan W. DNA aptamer-micelle as an efficient detection/delivery vehicle toward cancer cells. Proc Natl Acad Sci USA. 2010 Jan 5;107(1):5-10. doi: 10.1073/pnas.0909611107, PMID 20080797.

  127. Hicke BJ, Stephens AW, Gould T, Chang YF, Lynott CK, Heil J. Tumor targeting by an aptamer. J Nucl Med. 2006 Apr;47(4):668-78. PMID 16595502.

  128. Farokhzad OC, Jon S, Khademhosseini A, Tran TN, Lavan DA, Langer R. Nanoparticle-aptamer bioconjugates: a new approach for targeting prostate cancer cells. Cancer Res. 2004 Nov;64(21):7668-72. doi: 10.1158/0008-5472.CAN-04-2550, PMID 15520166.

  129. Peng L, Liang Y, Zhong X, Liang Z, Tian Y, Li S. Aptamer-conjugated gold nanoparticles targeting epidermal growth factor receptor variant III for the treatment of glioblastoma. Int J Nanomedicine. 2020 Feb 28;15:1363-72. doi: 10.2147/IJN.S238206, PMID 32184591.

  130. Charbgoo F, Alibolandi M, Taghdisi SM, Abnous K, Soltani F, Ramezani M. MUC1 aptamer-targeted DNA micelles for dual tumor therapy using doxorubicin and KLA peptide. Nanomedicine. 2018 Apr;14(3):685-97. doi: 10.1016/j.nano.2017.12.010, PMID 29317345.

  131. Yang H, Lu WL, Huang T, Chen QY, Gao J, Zhao Y. An aptamer-Fe3+ modified nanoparticle for lactate oxidation and tumor photodynamic therapy. Colloids Surf B Biointerfaces. 2018 Apr 1;164:192-200. doi: 10.1016/j.colsurfb.2018.01.045, PMID 29413596.

  132. Ni S, Zhuo Z, Pan Y, Yu Y, Li F, Liu J. Recent progress in aptamer discoveries and modifications for therapeutic applications. ACS Appl Mater Interfaces. 2021;13(8):9500-19. doi: 10.1021/acsami.0c05750, PMID 32603135.

  133. Baneshi M, Dadfarnia S, Shabani AMH, Sabbagh SK, Haghgoo S, Bardania H. A novel theranostic system of AS1411 aptamer-functionalized albumin nanoparticles loaded on iron oxide and gold nanoparticles for doxorubicin delivery. Int J Pharm. 2019 Jun 10;564:145-52. doi: 10.1016/j.ijpharm.2019.04.025, PMID 30978484.

  134. Xiao Z, Levy Nissenbaum E, Alexis F, Luptak A, Teply BA, Chan JM. Engineering of targeted nanoparticles for cancer therapy using internalizing aptamers isolated by cell-uptake selection. ACS Nano. 2012 Jan 24;6(1):696-704. doi: 10.1021/nn204165v, PMID 22214176.

  135. Amero P, Lokesh GLR, Chaudhari RR, Cardenas Zuniga R, Schubert T, Attia YM. Conversion of RNA aptamer into modified DNA aptamers provides for prolonged stability and enhanced antitumor activity. J Am Chem Soc. 2021 May;143(20):7655-70. doi: 10.1021/jacs.9b10460, PMID 33988982.

  136. Ng EW, Shima DT, Calias P, Cunningham ET, Guyer DR, Adamis AP. Pegaptanib, a targeted anti-VEGF aptamer for ocular vascular disease. Nat Rev Drug Discov. 2006 Feb;5(2):123-32. doi: 10.1038/nrd1955, PMID 16518379.

  137. Tekie FSM, Soleimani M, Zakerian A, Dinarvand M, Amini M, Dinarvand R. Glutathione responsive chitosan-thiolated dextran conjugated miR-145 nanoparticles targeted with AS1411 aptamer for cancer treatment. Carbohydr Polym. 2018 Dec 1;201:131-40. doi: 10.1016/j.carbpol.2018.08.060, PMID 30241804.

  138. Zhou J, Li H, Li S, Zaia J, Rossi JJ. Novel dual inhibitory function aptamer-siRNA delivery system for HIV-1 therapy. Mol Ther. 2008 Aug;16(8):1481-9. doi: 10.1038/mt.2008.92, PMID 18461053.

  139. Shieh YA, Yang SJ, Wei MF, Shieh MJ. Aptamer-based tumor-targeted drug delivery for photodynamic therapy. ACS Nano. 2010 Mar 23;4(3):1433-42. doi: 10.1021/nn901374b, PMID 20166743.

  140. Ludwig H, Weisel K, Petrucci MT, Leleu X, Cafro AM, Garderet L. Olaptesed pegol, an anti-CXCL12/SDF-1 spiegelmer, alone and with bortezomib–dexamethasone in relapsed/refractory multiple myeloma: a phase iia study. Leukemia. 2017 Apr;31(4):997-1000. doi: 10.1038/leu.2017.5, PMID 28074071.

  141. Soundararajan S, Wang L, Sridharan V, Chen W, Courtenay Luck N, Jones D. Plasma membrane nucleolin is a receptor for the anticancer aptamer AS1411 in MV4-11 leukemia cells. Mol Pharmacol. 2009 Nov;76(5):984-91. doi: 10.1124/mol.109.055947, PMID 19657047.

  142. Waldschmidt JM, Simon A, Wider D, Muller SJ, Follo M, Ihorst G, Decker S, Lorenz J, Chatterjee M, Azab AK. CXCL 12 and CXCR 7 are relevant targets to reverse cell adhesion-mediated drug resistance in multiple myeloma. Br J Haematol. 2017 Oct;179(1):36–49.

  143. Tao W, Zeng X, Wu J, Zhu X, Yu X, Zhang X. Polydopamine-based surface modification of novel nanoparticle-aptamer bioconjugates for in vivo breast cancer targeting and enhanced therapeutic effects. Theranostics. 2016 Feb 11;6(4):470-84. doi: 10.7150/thno.14184, PMID 26941841.

  144. Troisi R, Napolitano V, Spiridonova V, Russo Krauss I, Sica F. Several structural motifs cooperate in determining the highly effective anti-thrombin activity of NU172 aptamer. Nucleic Acids Res. 2018 Dec;46(22):12177-85. doi: 10.1093/nar/gky990, PMID 30357392.

  145. Xu L, He XY, Liu BY, Xu C, Ai SL, Zhuo RX. Aptamer-functionalized albumin-based nanoparticles for targeted drug delivery. Colloids Surf B Biointerfaces. 2018 Nov 1;171:24-30. doi: 10.1016/j.colsurfb.2018.07.008, PMID 30005287.

  146. Li H, Mu Y, Lu J, Wei W, Wan Y, Liu S. Target-cell-specific fluorescence silica Nanoprobes for imaging and theranostics of cancer cells. Anal Chem. 2014 Apr 1;86(7):3602-9. doi: 10.1021/ac500173d, PMID 24576151.

  147. Petrukhin K. Recent developments in agents for the treatment of age-related macular degeneration and Stargardt disease. Drug Deliv Chall Novel Ther Approaches Retin Dis. 2020 Jul;105:125-60.

  148. Zhang Y, Zhao J, Sun J, Huang L, Li Q. Targeting lung cancer initiating cells by all-trans retinoic acid-loaded lipid-PLGA nanoparticles with CD133 aptamers. Exp Ther Med. 2018 Dec;16(6):4639-49. doi: 10.3892/etm.2018.6762, PMID 30542415.

  149. Dong J, Cao Y, Shen H, Ma Q, Mao S, Li S. EGFR aptamer-conjugated liposome-polycation-DNA complex for targeted delivery of SATB1 small interfering RNA to choriocarcinoma cells. Biomed Pharmacother. 2018 Nov;107:849-59. doi: 10.1016/j.biopha.2018.08.042, PMID 30142547.

  150. Shieh YA, Yang SJ, Wei MF, Shieh MJ. Aptamer-based tumor-targeted drug delivery for photodynamic therapy. ACS Nano. 2010 Mar 23;4(3):1433-42. doi: 10.1021/nn901374b, PMID 20166743.

  151. Mayr FB, Knobl P, Jilma B, Siller Matula JM, Wagner PG, Schaub RG, Gilbert JC, Jilma Stohlawetz Z. The aptamer ARC1779 blocks von Willebrandfactor–dependent platelet function in patients with thrombotic thrombocytopenic purpura ex vivo. Transfusion. 2010 May;50(5):1079–87.

  152. Li N, Larson T, Nguyen HH, Sokolov KV, Ellington AD. Correction: directed evolution of gold nanoparticle delivery to cells. Chem Commun (Camb). 2020 Apr 21;56(31):4368. doi: 10.1039/d0cc90149k, PMID 32242585.

  153. Grabowska Jadach I, Kalinowska D, Drozd M, Pietrzak M. Synthesis, characterization and application of plasmonic hollow gold nanoshells in a photothermal therapy-new particles for theranostics. Biomed Pharmacother. 2019 Mar;111:1147-55. doi: 10.1016/j.biopha.2019.01.037, PMID 30841428.

  154. Matsunaga KI, Kimoto M, Hirao I. High-affinity DNA aptamer generation targeting von Willebrand factor A1-domain by genetic alphabet expansion for systematic evolution of ligands by exponential enrichment using two types of libraries composed of five different bases. J Am Chem Soc. 2017 Jan;139(1):324-34. doi: 10.1021/jacs.6b10767, PMID 27966933.

  155. Jaffe GJ, Eliott D, Wells JA, Prenner JL, Papp A, Patel S. A phase 1 study of intravitreous E10030 in combination with ranibizumab in neovascular age-related macular degeneration. Ophthalmology. 2016 Jan;123(1):78-85. doi: 10.1016/j.ophtha.2015.09.004, PMID 26499921.

  156. Zou J, Shi M, Liu X, Jin C, Xing X, Qiu L. Aptamer-functionalized exosomes: elucidating the cellular uptake mechanism and the potential for cancer-targeted chemotherapy. Anal Chem. 2019 Feb 5;91(3):2425-30. doi: 10.1021/acs.analchem.8b05204, PMID 30620179.

  157. Bagalkot V, Gao X. siRNA-aptamer chimeras on nanoparticles: preserving targeting functionality for effective gene silencing. ACS Nano. 2011 Oct 25;5(10):8131-9. doi: 10.1021/nn202772p, PMID 21936502.

  158. Chen HY, Albert K, Wen CC, Hsieh PY, Chen SY, Huang NC. Multifunctional silver nanocluster-hybrid oligonucleotide vehicle for cell imaging and microRNA-targeted gene silencing. Colloids Surf B Biointerfaces. 2017;152:423-31. doi: 10.1016/j.colsurfb.2017.01.048, PMID 28171795.

  159. Chen CH, Dellamaggiore KR, Ouellette CP, Sedano CD, Lizadjohry M, Chernis GA. Aptamer-based endocytosis of a lysosomal enzyme. Proc Natl Acad Sci USA. 2008 Oct 14;105(41):15908-13. doi: 10.1073/pnas.0808360105, PMID 18838694.

  160. Pascual L, Cerqueira Coutinho C. Garcıa Fernandez A, de Luis B, Bernardes ES, Albernaz MS, Missailidis S, Martınez Manez R, Santos Oliveira R, Orzaez MJNN. MUC1 aptamer-capped mesoporous silica nanoparticles for controlled drug delivery and radio-imaging applications. Biol Med. 2017 Nov;13(8):2495-505.

  161. Yu MK, Kim D, Lee IH, So JS, Jeong YY, Jon S. Image-guided prostate cancer therapy using aptamer-functionalized thermally cross-linked superparamagnetic iron oxide nanoparticles. Small. 2011 Aug 8;7(15):2241-9. doi: 10.1002/smll.201100472, PMID 21648076.

  162. Monaco I, Camorani S, Colecchia D, Locatelli E, Calandro P, Oudin A. Aptamer functionalization of nanosystems for glioblastoma targeting through the blood-brain barrier. J Med Chem. 2017 May 25;60(10):4510-6. doi: 10.1021/acs.jmedchem.7b00527, PMID 28471660.

  163. Binaymotlagh R, Hajareh Haghighi FH, Aboutalebi F, Mirahmadi Zare SZ, Hadadzadeh H, Nasr Esfahani MHJN. Selective chemotherapy and imaging of colorectal and breast cancer cells by a modified MUC-1 aptamer conjugated to a poly (ethylene glycol)-dimethacrylate coated Fe3O4−AuNCs nanocomposite. New J Chem. 2019 Nov;43(1):238-48. doi: 10.1039/C8NJ04236E.

  164. Zhao C, Song X, Jin W, Wu F, Zhang Q, Zhang M. Image-guided cancer therapy using aptamer-functionalized cross-linked magnetic-responsive Fe3O4@carbon nanoparticles. Anal Chim Acta. 2019 May;1056:108-16. doi: 10.1016/j.aca.2018.12.045, PMID 30797451.

  165. Wu X, Tai Z, Zhu Q, Fan W, Ding B, Zhang W. Study on the prostate cancer-targeting mechanism of aptamer-modified nanoparticles and their potential anticancer effect in vivo. Int J Nanomedicine. 2014 Nov 21;9:5431-40. doi: 10.2147/IJN.S71101, PMID 25473281.

  166. Mosafer J, Abnous K, Tafaghodi M, Mokhtarzadeh A, Ramezani MJE. In vitro and in vivo evaluation of anti-nucleolin-targeted magnetic PLGA unnatural-base DNA aptamers targeting cancer cells. Molecular Therapy-Nucleic Acids Biopharmaceutics. 2017 Apr;14:158-70.

  167. Shi H, Ye X, He X, Wang K, Cui W, He D. Au@Ag/Au nanoparticles assembled with activatable aptamer probes as smart ”nano-doctors” for image-guided cancer thermotherapy. Nanoscale. 2014 May;6(15):8754-61. doi: 10.1039/C4NR01927J.

  168. Wen S, Miao X, Fan GC, Xu T, Jiang LP, Wu P. Aptamer-conjugated au nanocage/SiO2 core-shell bifunctional nanoprobes with high stability and biocompatibility for cellular SERS imaging and near-infrared photothermal therapy. ACS Sens. 2019 Feb;4(2):301-8. doi: 10.1021/acssensors.8b00682, PMID 30624040.

  169. Aravind A, Varghese SH, Veeranarayanan S, Mathew A, Nagaoka Y, Iwai S. Aptamer-labeled PLGA nanoparticles for targeting cancer cells. Cancer Nanotechnol. 2012;3(1-6):1-12. doi: 10.1007/s12645-011-0024-6, PMID 26069492.

  170. Li L, Hou J, Liu X, Guo Y, Wu Y, Zhang L. Nucleolin-targeting liposomes guided by aptamer AS1411 for the delivery of siRNA for the treatment of malignant melanomas. Biomaterials. 2014 Apr;35(12):3840-50. doi: 10.1016/j.biomaterials.2014.01.019, PMID 24486214.

  171. Yang L, Tseng YT, Suo G, Chen L, Yu J, Chiu WJ. Photothermal therapeutic response of cancer cells to aptamer-gold nanoparticle-hybridized graphene oxide under NIR illumination. ACS Appl Mater Interfaces. 2015 Mar;7(9):5097-106. doi: 10.1021/am508117e, PMID 25705789.

  172. Kolovskaya OS, Zamay TN, Zamay GS, Babkin VA, Medvedeva EN, Neverova NA. Aptamer-conjugated superparamagnetic Ferroarabinogalactan nanoparticles for targeted magnetodynamic therapy of cancer. Cancers. 2020 Jan;12(1):216. doi: 10.3390/cancers12010216, PMID 31952299.

  173. Ma J, Zhuang H, Zhuang Z, Lu Y, Xia R, Gan L. Development of docetaxel liposome surface modified with CD133 aptamers for lung cancer targeting. Artif Cells Nanomed Biotechnol. 2018 Dec;46(8):1864-71. doi: 10.1080/21691401.2017.1394874, PMID 29082764.

  174. Vandghanooni S, Eskandani M, Barar J, Omidi Y. AS1411 aptamer-decorated cisplatin-loaded poly(lactic-co-glycolic acid) nanoparticles for targeted therapy of miR-21-inhibited ovarian cancer cells. Nanomedicine (Lond). 2018 Nov;13(21):2729-58. doi: 10.2217/nnm-2018-0205, PMID 30394201.

  175. Moosavian SA, Abnous K, Badiee A, Jaafari MR. Improvement in the drug delivery and anti-tumor efficacy of pegylated liposomal doxorubicin by targeting RNA aptamers in mice bearing breast tumor model. Colloids Surf B Biointerfaces. 2016 Mar;139:228-36. doi: 10.1016/j.colsurfb.2015.12.009, PMID 26722819.

  176. Cadinoiu AN, Rata DM, Atanase LI, Daraba OM, Gherghel D, Vochita G. Aptamer-functionalized liposomes as a potential treatment for basal cell carcinoma. Polymers. 2019 Sep;11(9):1515. doi: 10.3390/polym11091515, PMID 31540426.

  177. Erin N, Dilmac S, Curry A, Duymuş O, Tanriover G, Prodeus A. CD200 mimetic aptamer PEG-M49 markedly increases the therapeutic effects of pegylated liposomal doxorubicin in a mouse model of metastatic breast carcinoma: an effect independent of CD200 receptor 1. Cancer Immunol Immunother. 2020;69(1):103-14. doi: 10.1007/s00262-019-02444-3, PMID 31811336.

  178. Mashreghi M, Zamani P, Moosavian SA, Jaafari MR. Anti-Epcam aptamer (Syl3c)-functionalized liposome for targeted delivery of doxorubicin: in vitro and in vivo antitumor studies in mice bearing C26 colon carcinoma. Nanoscale Res Lett. 2020 May;15(1):101. doi: 10.1186/s11671-020-03334-9, PMID 32383027.

  179. Varnamkhasti BS, Hosseinzadeh H, Azhdarzadeh M, Vafaei SY, Esfandyari-Manesh M, Mirzaie ZH. Protein corona hampers targeting potential of MUC1 aptamer functionalized SN-38 core-shell nanoparticles. Int J Pharm. 2015 Oct 15;494(1):430-44. doi: 10.1016/j.ijpharm.2015.08.060, PMID 26315125.

  180. Wang H, Zhu Z, Zhang G, Lin F, Liu Y, Zhang Y. AS1411 Aptamer/hyaluronic acid-biofunctionalized microemulsion co-loading shikonin and docetaxel for enhanced antiglioma therapy. J Pharm Sci. 2019;108(11):3684-94. doi: 10.1016/j.xphs.2019.08.017, PMID 31465736.

  181. Zhao Y, Xu J, Le VM, Gong Q, Li S, Gao F. EpCAM aptamer-functionalized cationic liposome-based nanoparticles loaded with miR-139-5p for targeted therapy in colorectal cancer. Mol Pharm. 2019;16(11):4696-710. doi: 10.1021/acs.molpharmaceut.9b00867, PMID 31589818.

  182. Song X, Ren Y, Zhang J, Wang G, Han X, Zheng W. Targeted delivery of doxorubicin to breast cancer cells by aptamer functionalized DOTAP/DOPE liposomes. Oncol Rep. 2015 Oct;34(4):1953-60. doi: 10.3892/or.2015.4136, PMID 26238192.

  183. Atabi F, Mousavi Gargari SL, Hashemi M, Yaghmaei P. Doxorubicin loaded DNA aptamer linked myristilated chitosan nanogel for targeted drug delivery to prostate cancer. Iran J Pharm Res. 2017 Aug;16(1):35-49. PMID 28496460.

  184. Ding L, Li J, Wu C, Yan F, Li X, Zhang S. A self-assembled RNA-triple helix hydrogel drug delivery system targeting triple-negative breast cancer. J Mater Chem B. 2020 Nov;8(16):3527-33. doi: 10.1039/c9tb01610d, PMID 31737891.

  185. Pan Q, Nie C, Hu Y, Yi J, Liu C, Zhang J. Aptamer-functionalized DNA origami for targeted codelivery of antisense oligonucleotides and doxorubicin to enhance therapy in drug-resistant cancer cells. ACS Appl Mater Interfaces. 2020 Jan 8;12(1):400-9. doi: 10.1021/acsami.9b20707, PMID 31815420.

  186. Zhang L, Wang S, Yang Z, Hoshika S, Xie S, Li J. An aptamer-nanotrain assembled from six-letter DNA delivers doxorubicin selectively to liver cancer cells. Angew Chem Int Ed Engl. 2020 Jan 7;59(2):663-8. doi: 10.1002/anie.201909691, PMID 31650689.

  187. Varnamkhasti BS, Hosseinzadeh H, Azhdarzadeh M, Vafaei SY, Esfandyari-Manesh M, Mirzaie ZH. Protein corona hampers targeting potential of MUC1 aptamer functionalized SN-38 core–shell nanoparticles. Int J Pharm. 2015 Oct;494(1):430-44. doi: 10.1016/j.ijpharm.2015.08.060, PMID 26315125.

  188. Yang Y, Zhao W, Tan W, Lai Z, Fang D, Jiang L. An efficient cell-targeting drug delivery system based on aptamer-modified mesoporous silica nanoparticles. Nanoscale Res Lett. 2019;14(1):390. doi: 10.1186/s11671-019-3208-3, PMID 31872318.

  189. Esfandyari Manesh M, Mohammadi A, Atyabi F, Nabavi SM, Ebrahimi SM, Shahmoradi E. Specific targeting delivery to MUC1 overexpressing tumors by albumin-chitosan nanoparticles conjugated to DNA aptamer. Int J Pharm. 2016 Dec;515(1-2):607-15. doi: 10.1016/j.ijpharm.2016.10.066, PMID 27989825.

  190. Barzegar Behrooz A, Nabavizadeh F, Adiban J, Shafiee Ardestani M, Vahabpour R, Aghasadeghi MR. Smart bomb AS1411 aptamer-functionalized/PAMAM dendrimer nanocarriers for targeted drug delivery in the treatment of gastric cancer. Clin Exp Pharmacol Physiol. 2017 Jan;44(1):41-51. doi: 10.1111/1440-1681.12670, PMID 27626786.

  191. Alibolandi M, Taghdisi SM, Ramezani P, Hosseini Shamili FH, Farzad SA, Abnous K. Smart AS1411-aptamer conjugated pegylated PAMAM dendrimer for the superior delivery of camptothecin to colon adenocarcinoma in vitro and in vivo. Int J Pharm. 2017 Mar;519(1-2):352-64. doi: 10.1016/j.ijpharm.2017.01.044, PMID 28126548.

  192. Chen H, Tian J, Liu D, He W, Guo Z. Dual aptamer modified dendrigraft poly-l-lysine nanoparticles for overcoming multi-drug resistance through mitochondrial targeting. J Mater Chem B. 2017 Dec;5(5):972-9. doi: 10.1039/c6tb02714h, PMID 32263875.

  193. Lee IH, An S, Yu MK, Kwon HK, Im SH, Jon S. Targeted chemoimmunotherapy using drug-loaded aptamer–dendrimer bioconjugates. J Control Release. 2011;155(3):435-41. doi: 10.1016/j.jconrel.2011.05.025, PMID 21641946.

  194. Zhou J, Soontornworajit B, Martin J, Sullenger BA, Gilboa E, Wang Y. A hybrid DNA aptamer-dendrimer nanomaterial for targeted cell labeling. Macromol Biosci. 2009 Sep;9(9):831-5. doi: 10.1002/mabi.200900046, PMID 19434675.

  195. Ryou SM, Yeom JH, Kang HJ, Won M, Kim JS, Lee B. Gold nanoparticle-DNA aptamer composites as a universal carrier for in vivo delivery of biologically functional proteins. J Control Release. 2014 Dec 28;196:287-94. doi: 10.1016/j.jconrel.2014.10.021, PMID 25450403.

  196. Wang H, Zhao X, Guo C, Ren D, Zhao Y, Xiao W. Aptamer-dendrimer bioconjugates for targeted delivery of miR-34a expressing plasmid and antitumor effects in non-small cell lung cancer cells. PLOS ONE. 2015 Sep;10(9):e0139136. doi: 10.1371/journal.pone.0139136, PMID 26406332.

  197. Ayatollahi S, Salmasi Z, Hashemi M, Askarian S, Oskuee RK, Abnous K. Aptamer-targeted delivery of Bcl-xL shRNA using alkyl modified PAMAM dendrimers into lung cancer cells. Int J Biochem Cell Biol. 2017 Nov;92:210-7. doi: 10.1016/j.biocel.2017.10.005, PMID 29031805.

  198. Bahreyni A, Alibolandi M, Ramezani M, Sarafan Sadeghi A, Abnous K, Taghdisi SM. A novel MUC1 aptamer-modified PLGA-epirubicin-PβAE-antimir-21 nanocomplex platform for targeted co-delivery of anticancer agents in vitro and in vivo. Colloids Surf B Biointerfaces. 2019 Mar 1;175:231-8. doi: 10.1016/j.colsurfb.2018.12.006, PMID 30537619.

  199. Li X, Yu Y, Ji Q, Qiu L. Targeted delivery of anticancer drugs by aptamer AS1411 mediated pluronic F127/cyclodextrin-linked polymer composite micelles. Nanomed Nanotechnol Boil Med. 2015 Jan;11(1):175-84.

  200. Ghassami E, Varshosaz J, Jahanian Najafabadi A, Minaiyan M, Rajabi P, Hayati E. Pharmacokinetics and in vitro/in vivo antitumor efficacy of aptamer-targeted Ecoflex® nanoparticles for docetaxel delivery in ovarian cancer. Int J Nanomedicine. 2018 Jan 23;13:493-504. doi: 10.2147/IJN.S152474, PMID 29416331.

  201. Askarian S, Abnous K, Taghavi S, Oskuee RK, Ramezani M. Cellular delivery of shRNA using aptamer-conjugated PLL-alkyl-PEI nanoparticles. Colloids Surf B Biointerfaces. 2015 Dec;136:355-64. doi: 10.1016/j.colsurfb.2015.09.023, PMID 26433348.

  202. Subramanian N, Kanwar JR, Athalya PK, Janakiraman N, Khetan V, Kanwar RK. EpCAM aptamer mediated cancer cell specific delivery of EpCAM siRNA using polymeric nanocomplex. J Biomed Sci. 2015 Jan;22(4):4. doi: 10.1186/s12929-014-0108-9, PMID 25576037.

  203. Khezrian S, Khoee S, Caceres M. Synthesis of combinatorial Janus nanoparticles based on EpCAM-PEG/PCL for targeted therapy of human colorectal adenocarcinoma. J Biomedical Materials Res. 2020 Nov;108(11):2291-304. doi: 10.1002/jbm.a.36986.

  204. Xu W, Siddiqui IA, Nihal M, Pilla S, Rosenthal K, Mukhtar H. Aptamer-conjugated and doxorubicin-loaded unimolecular micelles for targeted therapy of prostate cancer. Biomaterials. 2013 Jul;34(21):5244-53. doi: 10.1016/j.biomaterials.2013.03.006, PMID 23582862.

  205. Jalalian SH, Ramezani M, Abnous K, Taghdisi SM. Targeted co-delivery of epirubicin and NAS-24 aptamer to cancer cells using selenium nanoparticles for enhancing tumor response in vitro and in vivo. Cancer Lett. 2018 Mar;416:87-93. doi: 10.1016/j.canlet.2017.12.023, PMID 29253524.

  206. Liu H, Sun N, Ding P, Chen C, Wu Z, Zhu W. Fabrication of aptamer modified TiO2 nanofibers for specific capture of circulating tumor cells. Colloids Surf B Biointerfaces. 2020 Jul;191:110985. doi: 10.1016/j.colsurfb.2020.110985, PMID 32247218.

  207. Saravanakumar K, Hu X, Shanmugam S, Chelliah R, Sekar P, Oh DH. Enhanced cancer therapy with pH-dependent and aptamer functionalized doxorubicin loaded polymeric (poly D, L-lactic-co-glycolic acid) nanoparticles. Arch Biochem Biophys. 2019 Aug 15;671:143-51. doi: 10.1016/j.abb.2019.07.004, PMID 31283911.

  208. Wang AZ, Bagalkot V, Vasilliou CC, Gu F, Alexis F, Zhang L. Superparamagnetic iron oxide nanoparticle-aptamer bioconjugates for combined prostate cancer imaging and therapy. ChemMedChem. 2008 Sep;3(9):1311-5. doi: 10.1002/cmdc.200800091, PMID 18613203.

  209. Jalalian SH, Taghdisi SM, Shahidi Hamedani NS, Kalat SAM, Lavaee P, Zandkarimi M. Epirubicin loaded super paramagnetic iron oxide nanoparticle-aptamer bioconjugate for combined colon cancer therapy and imaging in vivo. Eur J Pharm Sci. 2013 Oct;50(2):191-7. doi: 10.1016/j.ejps.2013.06.015, PMID 23835028.

  210. Wu C, Han D, Chen T, Peng L, Zhu G, You M. Building a multifunctional aptamer-based DNA nanoassembly for targeted cancer therapy. J Am Chem Soc. 2013 Nov;135(49):18644-50. doi: 10.1021/ja4094617, PMID 24245521.

  211. Li F, Mei H, Xie X, Zhang H, Liu J, Lv T. Aptamer-conjugated chitosan-anchored liposomal complexes for targeted delivery of erlotinib to EGFR-mutated lung cancer cells. AAPS J. 2017 May;19(3):814-26. doi: 10.1208/s12248-017-0057-9, PMID 28233244.

  212. Zhuang Y, Deng H, SuY, He L, Wang R, Tong G, He D, Zhu X. Aptamer-functionalized and backbone redox-responsive hyperbranched polymer for targeted drug delivery in cancer therapy. Biomacromolecules. 2016;(17):2050–62.

  213. Deng K, Hou Z, Li X, Li C, Zhang Y, Deng X. Aptamer-mediated up-conversion core/MOF shell nanocomposites for targeted drug delivery and cell imaging. Sci Rep. 2015 Jan 19;5:7851. doi: 10.1038/srep07851, PMID 25597762.

  214. Sakhtianchi R, Darvishi B, Mirzaie Z, Dorkoosh F, Shanehsazzadeh S, Dinarvand R. Pegylated magnetic mesoporous silica nanoparticles decorated with AS1411 aptamer as a targeting delivery system for cytotoxic agents. Pharm Dev Technol. 2019 Nov;24(9):1063-75. doi: 10.1080/10837450.2019.1569678, PMID 30654677.

  215. Guo W, Mashimo Y, Kobatake E, Mie M. Construction of DNA-displaying nanoparticles by enzymatic conjugation of DNA and elastin-like polypeptides using a replication initiation protein. Nanotechnology. 2020 Apr;31(25):255102. doi: 10.1088/1361-6528/ab8042, PMID 32176872.

  216. Saravanakumar K, Hu X, Shanmugam S, Chelliah R, Sekar P, Oh DH. Enhanced cancer therapy with pH-dependent and aptamer functionalized doxorubicin loaded polymeric (poly D, L-lactic-co-glycolic acid) nanoparticles. Arch Biochem Biophys. 2019 Aug;671:143-51. doi: 10.1016/j.abb.2019.07.004, PMID 31283911.

  217. Xu G, Yu X, Zhang J, Sheng Y, Liu G, Tao W. Robust aptamer–polydopamine-functionalized M-PLGA–TPGS nanoparticles for targeted delivery of docetaxel and enhanced cervical cancer therapy. Int J Nanomedicine. 2016 Jun;11:2953-65. doi: 10.2147/IJN.S103513, PMID 27382282.

  218. Zeng Z, Tung CH, Zu Y. Aptamer-equipped protamine nanomedicine for precision lymphoma therapy. Cancers. 2020 Apr;12(4):780. doi: 10.3390/cancers12040780, PMID 32218299.

  219. Yao F, An Y, Li X, Li Z, Duan J, Yang XD. Targeted therapy of colon cancer by aptamer-guided Holliday junctions loaded with doxorubicin. Int J Nanomedicine. 2020 Mar;15:2119-29. doi: 10.2147/IJN.S240083, PMID 32280210.

  220. Mie M, Matsumoto R, Mashimo Y, Cass AEG, Kobatake E. Development of drug-loaded protein nanoparticles displaying enzymatically-conjugated DNA aptamers for cancer cell targeting. Mol Biol Rep. 2019;46(1):261-9. doi: 10.1007/s11033-018-4467-2, PMID 30421127.

  221. Zhang Y, Chang YQ, Han L, Zhang Y, Chen ML, Shu Y. Aptamer-anchored di-polymer shell-capped mesoporous carbon as a drug carrier for bi-trigger targeted drug delivery. J Mater Chem B. 2017 Sep 7;5(33):6882-9. doi: 10.1039/c7tb01528c, PMID 32264337.

  222. Perepelyuk M, Sacko K, Thangavel K, Shoyele SA. Evaluation of MUC1-aptamer functionalized hybrid nanoparticles for targeted delivery of miRNA-29b to nonsmall cell lung cancer. Mol Pharm. 2018 Mar;15(3):985-93. doi: 10.1021/acs.molpharmaceut.7b00900, PMID 29432024.

  223. Prusty DK, Adam V, Zadegan RM, Irsen S, Famulok M. Supramolecular aptamer nano-constructs for receptor-mediated targeting and light-triggered release of chemotherapeutics into cancer cells. Nat Commun. 2018 Feb;9(1):535. doi: 10.1038/s41467-018-02929-2, PMID 29416033.

  224. Taghdisi SM, Danesh NM, Ramezani M, Lavaee P, Jalalian SH, Robati RY. Double targeting and aptamer-assisted controlled release delivery of epirubicin to cancer cells by aptamers-based dendrimer in vitro and in vivo. Eur J Pharm Biopharm. 2016 May;102:152-8. doi: 10.1016/j.ejpb.2016.03.013, PMID 26987703.

  225. Chang M, Yang CS, Huang DM. Aptamer-conjugated DNA icosahedral nanoparticles as a carrier of doxorubicin for cancer therapy. ACS Nano. 2011 Aug;5(8):6156-63. doi: 10.1021/nn200693a, PMID 21732610.

  226. Zhu G, Zheng J, Song E, Donovan M, Zhang K, Liu C. Self-assembled, aptamer-tethered DNA nanotrains for targeted transport of molecular drugs in cancer theranostics. Proc Natl Acad Sci USA. 2013 May;110(20):7998-8003. doi: 10.1073/pnas.1220817110, PMID 23630258.

  227. Xu Z, Ni R, Chen Y. Targeting breast cancer stem cells by a self-assembled, aptamer-conjugated DNA nanotrain with preloading doxorubicin. Int J Nanomedicine. 2019 Aug;14:6831-42. doi: 10.2147/IJN.S200482, PMID 31695364.

  228. Pi F, Zhang H, Li H, Thiviyanathan V, Gorenstein DG, Sood AK. RNA nanoparticles harboring annexin A2 aptamer can target ovarian cancer for tumor-specific doxorubicin delivery. Nanomedicine. 2017 Apr;13(3):1183-93. doi: 10.1016/j.nano.2016.11.015, PMID 27890659.

  229. Zhao N, Zeng Z, Zu Y. Self-assembled aptamer-nanomedicine for targeted chemotherapy and gene therapy. Small (Weinh Bergstr Ger). 2017 Jan;14(4):1702103.

  230. Shi S, Fu W, Lin S, Tian T, Li S, Shao X. Targeted and effective glioblastoma therapy via aptamer-modified tetrahedral framework nucleic acid-paclitaxel nanoconjugates that can pass the blood brain barrier. Nanomedicine. 2019 Oct;21:102061. doi: 10.1016/j.nano.2019.102061, PMID 31344499.

  231. Srivithya V, Roun H, Sekhar Babu M, Jae Hyung P, Sung Ha P. Aptamer-conjugated DNA nano-ring as the carrier of drug molecules. Nanotechnology. 2018 Mar;29(9):095602. doi: 10.1088/1361-6528/aaa3cb, PMID 29271356.

  232. Porciani D, Signore G, Marchetti L, Mereghetti P, Nifosì R, Beltram F. Two interconvertible folds modulate the activity of a DNA aptamer against transferrin receptor. Mol Ther Nucleic Acids. 2014 Jan;3(1):e144. doi: 10.1038/mtna.2013.71, PMID 24472870.

  233. Li N, Nguyen HH, Byrom M, Ellington AD. Inhibition of cell proliferation by an anti-EGFR aptamer. PLOS ONE. 2011 Jun;6(6):e20299. doi: 10.1371/journal.pone.0020299, PMID 21687663.

  234. Shangguan D, Li Y, Tang Z, Cao ZC, Chen HW, Mallikaratchy P. Aptamers evolved from live cells as effective molecular probes for cancer study. Proc Natl Acad Sci USA. 2006 Aug;103(32):11838-43. doi: 10.1073/pnas.0602615103, PMID 16873550.

  235. Smith JD, Cardwell LN, Porciani D, Nguyen AJ, Zhang R, Gallazzi F, Tata RR, Burke DH, Daniels MA, Ulery BD. Aptamer-displaying peptide amphiphile micelles as a cell-targeted delivery vehicle of peptide cargoes. Phys Biol. 2018;(15):065006.

  236. Li Z, Liu Z, Yin M, Yang X, Yuan Q, Ren J. Aptamer-capped multifunctional mesoporous strontium hydroxyapatite nanovehicle for cancer-cell-responsive drug delivery and imaging. Biomacromolecules. 2012 Dec 10;13(12):4257-63. doi: 10.1021/bm301563q, PMID 23140615.

  237. Ouyang C, Zhang S, Xue C, Yu X, Xu H, Wang Z. Precision-guided missile-like DNA nanostructure containing warhead and guidance control for aptamer-based targeted drug delivery into cancer cells in vitro and in vivo. J Am Chem Soc. 2020;142(3):1265-77. doi: 10.1021/jacs.9b09782, PMID 31895985.

  238. Yang S, Ren Z, Chen M, Wang Y, You B, Chen W. Nucleolin-targeting AS1411-Aptamer-modified graft polymeric micelle with dual pH/redox sensitivity designed to enhance tumor therapy through the codelivery of doxorubicin/TLR4 siRNA and suppression of invasion. Mol Pharm. 2018;15(1):314-25. doi: 10.1021/acs.molpharmaceut.7b01093, PMID 29250957.

  239. Chandra S, Michael Nguyen H, Wiltz K, Hall N, Chaudhry S, Olverson G. Aptamer-functionalized hybrid nanoparticles to enhance the delivery of doxorubicin into breast cancer cells by silencing P-glycoprotein. J Cancer Treatment Diagn. 2020;4(1):1-13. doi: 10.29245/2578-2967/2020/1.1176, PMID 32395707.

  240. Chen R, Sun P, Chu X, Pu X, Yang Y, Zhang N. Synergistic treatment of tumor by targeted biotherapy and chemotherapy via site-specific anchoring of aptamers on DNA nanotubes. Int J Nanomedicine. 2020 Feb 27;15:1309-20. doi: 10.2147/IJN.S225142, PMID 32161460.

  241. Li L, Xiang D, Shigdar S, Yang W, Li Q, Lin J. Epithelial cell adhesion molecule aptamer functionalized PLGA-lecithin-curcumin-PEG nanoparticles for targeted drug delivery to human colorectal adenocarcinoma cells. Int J Nanomedicine. 2014;9:1083-96. doi: 10.2147/IJN.S59779, PMID 24591829.

  242. Powell D, Chandra S, Dodson K, Shaheen F, Wiltz K, Ireland S. Aptamer-functionalized hybrid nanoparticle for the treatment of breast cancer. Eur J Pharm Biopharm. 2017 May;114:108-18. doi: 10.1016/j.ejpb.2017.01.011, PMID 28131717.

  243. Kim MW, Jeong HY, Kang SJ, Jeong IH, Choi MJ, You YM. Anti-EGF receptor aptamer-guided co-delivery of anti-cancer siRNAs and quantum dots for theranostics of triple-negative breast cancer. Theranostics. 2019 Jan 25;9(3):837-52. doi: 10.7150/thno.30228, PMID 30809312.

  244. Zhao J, Liu P, Ma J, Li D, Yang H, Chen W. Enhancement of radiosensitization by silver nanoparticles functionalized with polyethylene glycol and aptamer As1411 for glioma irradiation therapy. Int J Nanomedicine. 2019 Dec 2;14:9483-96. doi: 10.2147/IJN.S224160, PMID 31819445.

  245. Zaimy MA, Jebali A, Bazrafshan B, Mehrtashfar S, Shabani S, Tavakoli A. Coinhibition of overexpressed genes in acute myeloid leukemia subtype M2 by gold nanoparticles functionalized with five antisense oligonucleotides and one anti-CD33(+)/CD34(+) aptamer. Cancer Gene Ther. 2016 Sep;23(9):315-20. doi: 10.1038/cgt.2016.33, PMID 27514505.

  246. Yazdian Robati R, Arab A, Ramezani M, Rafatpanah H, Bahreyni A, Nabavinia MS, Abnous K, Taghdisi SM. Smart aptamer-modified calcium carbonate nanoparticles for controlled release and targeted delivery of epirubicin and melittin into cancer cells in vitro and in vivo. Drug Dev Ind Pharm. 2019 Apr;45(4):603-10.

  247. Guo X, Zhu X, Gao J, Liu D, Dong C, Jin X. PLGA nanoparticles with CD133 aptamers for targeted delivery and sustained release of propranolol to hemangioma. Nanomedicine (Lond). 2017 Nov;12(21):2611-24. doi: 10.2217/nnm-2017-0130, PMID 28960167.

  248. He XY, Ren XH, Peng Y, Zhang JP, Ai SL, Liu BY. Aptamer/peptide-functionalized genome-editing system for effective immune restoration through reversal of PD-L1-mediated cancer immunosuppression. Adv Mater. 2020 Apr;32(17):e2000208. doi: 10.1002/adma.202000208, PMID 32147886.

  249. Chen WH, Yang Sung S, Fadeev M, Cecconello A, Nechushtai R, Willner I. Targeted VEGF-triggered release of an anti-cancer drug from aptamer-functionalized metal-organic framework nanoparticles. Nanoscale. 2018 Mar 8;10(10):4650-7. doi: 10.1039/c8nr00193f, PMID 29465130.

  250. Zhao Q, Li J, Wu B, Shang Y, Huang X, Dong H. Smart biomimetic nanocomposites mediate mitochondrial outcome through aerobic glycolysis reprogramming: a promising treatment for lymphoma. ACS Appl Mater Interfaces. 2020 May 20;12(20):22687-701. doi: 10.1021/acsami.0c05763, PMID 32330381.

  251. Lin HC, Li WT, Madanayake TW, Tao C, Niu Q, Yan SQ. Aptamer-guided upconversion nanoplatform for targeted drug delivery and near-infrared light-triggered photodynamic therapy. J Biomater Appl. 2020 Jan;34(6):875-88. doi: 10.1177/0885328219882152, PMID 31623518.

  252. Wang T, Luo Y, Lv H, Wang J, Zhang Y, Pei R. Aptamer-based erythrocyte-derived mimic vesicles loaded with siRNA and doxorubicin for the targeted treatment of multidrug-resistant tumors. ACS Appl Mater Interfaces. 2019 Dec 11;11(49):45455-66. doi: 10.1021/acsami.9b16637, PMID 31718159.

  253. Zhao Y, Wang J, Cai X, Ding P, Lv H, Pei R. Metal-organic frameworks with enhanced photodynamic therapy: synthesis, erythrocyte membrane camouflage, and aptamer-targeted aggregation. ACS Appl Mater Interfaces. 2020 May 27;12(21):23697-706. doi: 10.1021/acsami.0c04363, PMID 32362109.

  254. Chan MH, Huang WT, Wang J, Liu RS, Hsiao M. Next-generation cancer-specific hybrid theranostic nanomaterials: MAGE-A3 NIR persistent luminescence nanoparticles conjugated to afatinib for in situ suppression of lung adenocarcinoma growth and metastasis. Adv Sci (Weinh). 2020 Mar 14;7(9):1903741. doi: 10.1002/advs.201903741, PMID 32382487.

  255. Jiang J, Chen H, Yu C, Zhang Y, Chen M, Tian S. The promotion of salinomycin delivery to hepatocellular carcinoma cells through EGFR and CD133 aptamers conjugation by PLGA nanoparticles. Nanomedicine (Lond). 2015 Jul;10(12):1863-79. doi: 10.2217/nnm.15.43, PMID 26139123.

  256. ClinicalTrials.gov. Available from: https://clinicaltrials.gov/ct2/show/NCT02686658?term=aptamer&rank=4. [Last accessed on 02 Feb 2016]

  257. ClinicalTrials.gov. Available from: https://clinicaltrials.gov/ct2/show/NCT01547897?term=NOX-E36&rank=3. [Last accessed on 27 Feb 2012]

  258. ClinicalTrials.gov. Vol. 2. Available from: https://clinicaltrials.gov/ct2/show/NCT01848106?term=REG1&rank. [Last accessed on 02 May 2013]

  259. Sundaram P, Kurniawan H, Byrne ME, Wower J. Therapeutic RNA aptamers in clinical trials. Eur J Pharm Sci. 2013 Jan 23;48(1-2):259-71. doi: 10.1016/j.ejps.2012.10.014, PMID 23142634.

  260. Bae ON. Targeting von Willebrand factor as a novel anti-platelet therapy; application of ARC1779, an Anti-vWF aptamer, against thrombotic risk. Arch Pharm Res. 2012 Oct;35(10):1693-9. doi: 10.1007/s12272-012-1000-3, PMID 23139119.

  261. Mayer G, Rohrbach F, Potzsch B, Muller J. Aptamer-based modulation of blood coagulation. Hamostaseologie. 2011 Nov;31(4):258-63. doi: 10.5482/ha-1156, PMID 22065102.

  262. Esposito CL, Catuogno S, de Franciscis V, Cerchia L. New insight into clinical development of nucleic acid aptamers. Discov Med. 2011 Jun;11(61):487-96. PMID 21712014.

  263. Cerchia L, Esposito CL, Camorani S, Catuogno S, Franciscis V. Coupling aptamers to short interfering RNAs as therapeutics. Pharmaceuticals (Basel). 2011 Oct 27;4(11):1434-49. doi: 10.3390/ph4111434, PMID 27721331.

  264. Byun J. Recent progress and opportunities for nucleic acid aptamers. Life (Basel). 2021 Feb 28;11(3):193. doi: 10.3390/life11030193, PMID 33671039.