Abstract
Aptamers, as a kind of small-molecule nucleic acid, have attracted much attention since their discovery. Compared with biological reagents such as antibodies, aptamers have the advantages of small molecular weight, low immunogenicity, low cost, and easy modification. At present, aptamers are mainly used in disease biomarker discovery, disease diagnosis, treatment, and targeted drug delivery vectors. In the process of screening and optimizing aptamers, it is found that there are still many problems need to be solved such as the design of the library, optimization of screening conditions, the truncation of screened aptamer, and the stability and toxicity of the aptamer. In recent years, the incidence of liver-related diseases is increasing year by year and the treatment measures are relatively lacking, which has attracted the people’s attention in the application of aptamers in liver diseases. This article mainly summarizes the research status of aptamers in disease diagnosis and treatment, especially focusing on the application of aptamers in liver diseases, showing the crucial significance of aptamers in the diagnosis and treatment of liver diseases, and the use of Discovery Studio software to find the binding target and sequence of aptamers, and explore their possible interaction sites.
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Introduction
Nucleic acid aptamer also known as aptamer is a single-stranded DNA or RNA molecule, which is 20 to 100 nt in length. They were first isolated in the early 1990s by Tuerk and Gold using the Systematic Evolution of Ligands by Exponential Enrichment (SELEX) technique [1, 2]. Since its discovery, many aptamers have been screened [3, 4], compared with antibodies, aptamers have the unique advantages of low molecular weight, low cost, easy chemical modification, non-toxic, low immunogenicity, easy to penetrate tissue barrier, and multi-target sites (amino acids, peptides, proteins [4,5,6,7,8,9,10,11,12,13,14], antibiotics [15], cells [16,17,18,19], viruses [20,21,22,23], bacteria [24, 25], ions [26], etc.), so it has been paid more and more attention. Different diseases have different specific targets, even the same disease also has a number of different targets, such as in the progress of liver fibrosis, TLR4, inflammatory cytokines, and TGF-beta are associated with fibrosis process, and only specific monoclonal antibody against a target cannot satisfy all the targets [27], whereas aptamers could overcome this difficulty.
Some diseases of liver, such as tumors and liver fibrosis, usually have no obvious clinical symptoms in the early stage, and need to rely on the gold standard of liver biopsy for diagnosis [28]. However, due to its high cost and aggressiveness, few patients are willing to undergo liver tissue biopsy at an early stage. Therefore, it is necessary to find a diagnostic method with low invasiveness and high specificity. Previous experimental studies have demonstrated the multifaceted potential of aptamers in both liver disease diagnosis and targeted drug delivery [29], thereby offering a novel approach for the diagnosis and treatment of liver-related diseases [30].
However, aptamers have some limitations and uncertainties in the diagnosis and treatment of diseases. A series of partial potential biomarkers have been obtained through modern genomics, proteomics, single-cell sequencing analysis, and other technologies, but they are rarely applied in clinical diagnosis and treatment due to their low specificity. Though, screening through some biomarkers have obtained corresponding aptamers through screening, such as Sgc8 targeting PTK7 [31], Pegaptanib targeting VEGF [32], and AS1411 targeting nucleolin [33], additionally, a series of aptamers and corresponding target proteins have been identified so far. Due to the difference between protein purification and its original state, the mechanism of action of aptamers and target proteins has not been fully confirmed. At the same time, many aptamers are obtained by cell-SELEX technology screening, and the target is the whole cell. The specific molecular targets and binding methods are still unclear. However, if these limitations can be solved, the application of aptamers will make breakthrough progress.
So, the article summarizes the recent progress and current situation of aptamers in the diagnosis and treatment of diseases, especially in liver disease, to provide advice for screening and application of aptamers in the future.
Update Patented Aptamer (1990–Present)
Recent Progress and Status of Aptamer
Aptamers have been widely concerned in various fields because of their high affinity, strong specificity, and strong stability in binding to targets [34]. Since the first aptamer was discovered, a large number of aptamers have been screened and optimized, and aptamers have promoted the development of basic research on biosensors, drug delivery systems, and disease diagnosis systems [35]. At present, the application of aptamers in medicine is mainly in the diagnosis and treatment of cancers. For example, the aptamer drug supported by the US FDA on the market at present is Macugen (Pegaptanib), an RNA aptamer targeting vascular endothelial growth factor (VEGF), which is applied to the treatment of eczema-related macular degeneration [36]. In SELEX screening, the performance of aptamers such as those targeting proteins may not be better than those obtained by targeting cells because the target molecules in cell-SELEX are closer to the original state of the in vivo environment [37].
Due to the simplicity of aptamer screening procedures and principles, a significant number of aptamers have been screened and patented. However, there is a limited availability of aptamers for biosensors, diagnostic probes, and therapeutic reagents, possibly due to challenges in post-screening modification and optimization [38]. By conducting searches on patent websites, one can gain insights into the quantity and development trends of aptamers in recent years. The results are depicted in Fig. 1, which indicates a gradual increase in the annual number of patent applications for liver disease-specific aptamers, highlighting their promising application prospects. Figure S1 of supply materials also presents an overview of the total number of aptamer patents since 2014.
The Aptamers are Currently in Clinical Trials
The aptamer can be optimized by truncating their sequences to reduce molecular weight and improve binding affinity, and can also be combined with high molecular weight fragments such as polyethylene glycol [39], cholesterol [40], protein [41], or nanomaterials [42] to prolong renal excretion. After sequence truncation and conjugation, modification at nucleotide ribose 2 position with –O–Me, –NH2, –F, etc., can prevent nuclease degradation [43]. Aptamer research is not going well in ongoing clinical trials, for example, E10030 inhibits fibroblast proliferation by blocking platelet-derived growth factor B chain (PDGF-B), and was declared a failure in phase III in august 2017, because E10030 combined with Ranibizumab did not prove to be more effective than Ranibizumab alone. Another example is the use of aptamer REG1 for anticoagulation therapy which was terminated in the trial due to severe allergic reactions [33]. Despite these difficulties, a number of aptamers are currently in clinical trials for the treatment of ocular diseases, thrombotic and vascular diseases, and cancers [44]. In terms of drug delivery, aptamers can replace other transporters for targeted delivery of drugs. For example, an aptamer specific for transferrin receptor CD71 (TfR) can replace transferrin and play an alternative role in cellular imaging or targeted drug delivery [45]. It can be used as a diagnostic reagent for biosensors by hybridization with DNA, RNA, peptides, or nanomaterials for specific targeting and imaging [46]. Clinical trials of aptamers can be found on https://clinicaltrials.gov/, a total of 44 aptamers and drug test the aptamer-related projects, the apatamers which have entered clinical trials included 12. Table 1 summarizes all aptamers that have entered clinical trials, including the diseases they have treated, the targets of action, and the clinical stages of investigation.
Discussion on the Use of Aptamers as Therapeutic Drugs
When applied to biological agents, aptamers are often used as therapeutic agents to regulate biological pathways and intervene in a variety of diseases [60]. The treatment of neovascular-related macular degeneration by intravitreal injection of aptamer E10030 in combination with Ranibizumab has proven successful in safety and efficacy despite failure in phase III clinical trials [47, 48]. The aptamer Pegaptanib, as an anti-VEGF antagonist, has been approved by the US FDA for intravitreal injection to block VEGF and thus treat AMD [61, 62], the first successful treatment for wet AMD. Although its use and results are not perfect, its benefits in treating AMD far outweighs its risks [63]. EYE001, a VEGF-targeting aptamers, has been shown in preclinical and clinical studies to improve vascular permeability and ocular neovascularization, with no significant side effects in a single-dose intravitreal injection in phase Ia clinical trials [64]. ARC1905, an aptamer that inhibits complement factor C5 to prevent terminal fragment structure by screening, is mainly used in the treatment of age-related macular degeneration, and a phase I study is currently under way to evaluate its safety and efficacy in combination with Lucentis [65, 66].
NOX-H94 is a structural mirror aptamer, which specifically binds hepcidin (Hep) and regulates chronic inflammatory anemia by blocking the biological function of Hep. As a non-natural mirror aptamer, it is not recognized by nuclease and immune system, and has certain safety [67]. NOX-E36 has a length of 40 nucleotides and can specifically bind to the proinflammatory chemokine C–C motif ligand 2 (CCL2). NOX-E36 is mainly used in the treatment of type 2 diabetes and has performed well in phase I clinical trials. It has an inhibitory effect on CCL2 without activating the innate immune system, which can be used as a new targeted therapy for diabetic kidney injury [51]. NOX-A12 is a novel pegylated oligonucleotide that specifically binds to the chemokine SDF-1 and is mainly used in the treatment of chronic lymphocytic leukemia. At present, its phase II clinical results show good safety and efficacy, and it can be used in combination with other targeted drugs to enhance efficacy and reduce drug side effects [68]. BAX499, formerly known as ARC19499, is an anti-tissue factor pathway inhibitor (TFPI) inhibitor. It mainly combines with TFPI to inhibit TFPI-mediated tissue factor pathway and shorten whole blood coagulation time. Furthermore, the bleeding of hemophilia patients is inhibited, so as to achieve the purpose of treatment [69]. AS1411 is an aptamer composed of 26 G-rich nucleotides, which can form a G-quadruplex structure. It is mainly used in cancer-targeted drug delivery, and has also been developed as a targeted drug or probe with high safety. At present, it is mainly connected with nanoparticles for targeted therapy or imaging of cancer [70]. As an anticoagulant, aptamer REG1 performs well against platelet thromboembolism, especially in cardiovascular disease. However, as an anticoagulant, its pharmacodynamics and immunogenicity are unpredictable, and it was eventually discontinued in clinical trials due to severe allergic reactions. Aptamer ARC1779 primarily inhibits von Willebrand factor (VWF), which causes thrombocytopenia in thrombosis. The current experimental results show that ARC1779 is well tolerated and safe, and has a good recovery effect on organ failure caused by thrombocytopenic purpura [71]. In the future, aptamers and their derived sensors and probes will provide multiple options for the diagnosis and treatment of diseases [44].
Cost-effectiveness analysis should also be considered in the application of aptamers. Using Pegaptanib as an exemplar, the FDA approved aptamer drug for AMD. AMD refers to age-related structural changes in the macular area of the eye, predominantly affecting individuals over 50 years old and representing a significant cause of blindness among older adults. Pegaptanib is a 28-base RNA aptamer employed as a vascular endothelial growth factor antagonist in AMD treatment. Current therapeutic options for AMD encompass ranibizumab, Pegaptanib, bevacizumab, and PDT with verteporfin. Studies have demonstrated that ranibizumab is considered the most cost-effective among approved regimens for treating AMD [72]. However, UK-based analysis revealed that Pegaptanib exhibited similar cost-effectiveness compared to best supportive care over a decade-long timeframe [73]. Nevertheless, it should be noted that the cost-effectiveness of Pegaptanib varied considerably depending on disease stage and time horizon [72, 74, 75].
Discussion on the Use of Aptamers as Drug Delivery Systems
Aptamer can be used not only as a drug directly but also as a drug carrier to deliver drugs directly to cells by coupling drugs such as siRNA, decoy ODN, and micro-RNA [76]. Existing RNA, DNA aptamers, and siRNAs are covalently or non-covalently combined to form chimeras, and modified, such as polyethylene glycol (PEG), to prolong degradation time and improve their bioavailability in vivo [77], while its side effects are significantly lower than those of chemotherapy and radiotherapy drugs [60, 65]. The aptamer Sgc8, which is currently in clinical trials, can target PTK7 as a potential drug for the treatment of malignant hematological diseases, solid tumors, and other diseases [78]. However, the development of aptamers has been questioned due to many setbacks in clinical trials [79]. One of the important issues is the synthesis and modification of aptamers. The synthesis of long sequence aptamers, especially RNA, is very difficult, and some special modifications can also increase the cost, limiting the clinical application of aptamers [76]. With the development of computer technology, molecular simulation technology can realize the prediction of chemical synthesis, modification, and structure. It is believed that the application of aptamers will make greater progress in the near future.
Application of Aptamer in Liver Disease
Liver Disease-Related Biomarkers
Liver is the main metabolic organ of human body. Liver diseases are usually triggered by the death of hepatocytes and progresses to hepatitis, fibrosis, cirrhosis, and liver cancer. At present, liver diseases mainly include acute liver diseases caused by food poisoning and infection, and chronic liver diseases caused by viral infection, fatty liver, alcoholic hepatitis, etc. [80]. In different liver injuries, there may appear many different biomarkers. Some of these specific markers play an important role in the diagnosis and targeted therapy of liver disease. ALT and AST are the most common biomarkers with significantly increased expression after liver injury, but lack specificity [81]. Other common biomarkers, such as K18, HMGB1, and micro-RNAs, also sensitively reflect liver injury. Moreover, combined with complementary markers, it can be used as a commonly used diagnostic index to effectively diagnose liver diseases caused by various factors [80]. Table S1 (shown in supply materials) summarizes the current biomarkers in the liver diseases process and Table 2 concludes the aptamers of known biomarkers obtained by screening which is used in liver diseases. But at present, maybe there are many studies on specific markers of liver cancer, so the current research on the applications of aptamers in the diagnosis and treatment of liver diseases is mainly aimed at liver cancers, such as develop a label-free microcantilever array aptasensor to detect HepG2 cells and to provide a simple method for the detection of liver cancer cells [82], use an aptamer-nanotrain to deliver doxorubicin selectively to liver cancer cells [83]. As for other kinds of liver diseases, TNF-α-targeting aptamer can attenuate the degree of hepatocyte damage and potentiate early regeneration of the liver tissues in TNF-α-mediated acute liver failure [30], and aptamer-functionalized ultrasound nanobubbles with resveratrol and ultra-small copper-based nanoparticles can treat non-alcoholic fatty liver diseases [84].
Aptamers are Used in the Diagnosis and Therapy of Liver Cancer
Cancer may not show symptoms in its early stages, which prevents timely diagnosis and treatment of cancer at an early stage. If in the early stages of cancer, biomarkers have emerged, then it is of great significance to screen aptamers targeting biomarkers as early tumor-specific diagnostic and therapeutic reagents. As probes, aptamers have better specificity and sensitivity than AFP, CEA, and other biomarkers for diagnosis [116]. Liver cancer is one of the five most common cancers in the world, among which HCC is the most common [117]. The traditional treatment strategy for HCC is surgery, but the recurrence rate is as high as 70%. Liver cancer stem cells (LCSC) have been found to have a great relationship with the growth, transformation, and metastasis of liver cancer [118]. Therefore, the main treatment direction is to find specific markers of LCSC as therapeutic targets for targeted drugs. Table 2 presents a comprehensive compilation of 22 aptamers, which have been identified as valuable diagnostic, therapeutic, and targeted delivery tools for liver cancer. Among them, the aptamer CL-4RNV616 specifically targets the epidermal growth factor receptor (EGFR), which is highly expressed in many cancers and is considered a prognostic indicator of cancer [119]. The specific recognition of EGFR protein in tumor cells can be used as a targeted probe for early cancer detection, but the binding ability of MDA-MB-231 breast cancer cells, hum-7 liver cancer cells, and U87MG glioma cells suggests non-specific cell recognition [107].
Aptamers are Used in Early Diagnosis of Liver Fibrosis
Liver fibrosis is an intermediate process of liver injury and inflammation caused by hepatitis virus infection, alcohol abuse, immune response, drug and chemical damage, and then develops into chronic progressive liver disease. During liver injury, inflammation, and repair, hepatic stellate cells (HSCs) located in the perisinusoidal space are activated and transformed into myofibroblasts (MFCS). MFCS produce large amounts of collagen, mainly extracellular matrix (ECM), resulting in liver fibrosis [120, 121]. Various cytokines and related signaling pathways in the development of liver fibrosis, as well as the pathways of stellate cell clearance (apoptosis, senescence, recovery to inactivation), have been clearly elucidated. Liver fibrosis eventually develops into cirrhosis and liver cancer. Liver fibrosis has been shown to be reversible, so treatment of liver fibrosis can effectively prevent cirrhosis and liver cancer [122]. At present, RNA interference (RNAi) has been studied for the treatment of liver fibrosis, but its targeting and effectiveness into the body are poor, so it is necessary to find different vectors for siRNA delivery [123]. At present, the diagnosis of liver fibrosis mainly depends on pathology and imaging examination. Although molecular markers of liver fibrosis are abundant [124], there are very few aptamers related to liver fibrosis. This is mainly because the progress of liver fibrosis is affected by many factors comprehensive, so it is used for the screening of aptamers of liver fibrosis and the application may be limited by a lot of restrictions, in Table 2, we only found two relevant aptamers, which is primarily on liver fibrosis in the process of increased protein expression on HSCs, and the treatment of siRNA has yet to achieve good results. The aptamer 20 obtained by insulin-like growth factor II receptor (IGFIIR) targeting performed well at the cellular level after carrying PCBP2 siRNA. Although IGFIIR is a non-specific marker of HSCs, it is overexpressed in activated HSCs and therefore was selected as the target. Aptamer-20 carrying siRNA into HSC-T6 can trigger the silencing effect and restore the activated HSC-T6 to the quiescent state [111]. For the screening of HSCs aptamer, in addition to HSC-T6, human LX-2 cell line or primary stellate cells isolated directly from mice can also be selected as positive screening cells, and better results will be obtained.
Aptamers are Used in Diagnosis and Therapeutic of Liver Injury
Liver injury mainly includes trauma, acute injury caused by drugs, and chronic injury caused by viral infection. The main treatment for liver injury is liver transplantation, or the prevention and treatment of complications such as liver failure, without other specific treatment [125]. In the case of acute injury, hepatocyte necrosis leads to the secretion of TNF and the elevation of acute CRP. During liver failure, aptamer targets TNF and CRP mainly by inhibiting TNF and tracking the site of CRP secretion, thereby blocking the inflammatory process and reducing and eliminating inflammation [109, 126]. However, neither of these two targets is specific and can be increased by stress in other inflammatory states. Acute liver failure is rare, so it may still be misdiagnosed in diagnosis and treatment. Chronic liver injury is mainly caused by hepatitis B virus (HBV), hepatitis C virus (HCV), influenza, and other viruses [127]. SARS-CoV-2 can also affect the liver, but the main reason may be drug-induced liver injury caused by the use of antiviral drugs such as lopinavir/ritonavir, rather than the virus itself, and the exact mechanism has not been proved [128]. At present, for HBV and other infections, long-term nucleotide surimi, which is well tolerated and has few side effects is used, and the main preventive measure is vaccination without infection [129]. New treatments are still being developed, and aptamers are good candidates to carry antiviral drugs that can effectively treat HBV.
Aptamers for Other Liver-Related Diseases
Many diseases can cause indirect damage to the liver in other ways. For example, cancer cells can migrate to the liver through the blood circulation and cause liver damage. Liver metastasis of cancer cells is more common than primary liver tumors, and liver metabolism is very vigorous. In the early stage of the disease, there are often no symptoms, and it is easy to miss the best treatment time [130]. At present, the main aim is to prevent the disease and reduce the involvement of the liver. Metron factor-1 (MF-1) has great potential to prevent some malignant diseases that are difficult to treat, including liver metastases, melanoma, gastrointestinal tumors, etc., because it inhibits angiogenesis and tumor metastasis [131].
Cells in the liver, including sinusoidal endothelial cells, HSCs, and kupff cells, communicate with cancer cells through complex cytokines that are potential therapeutic targets [132]. Schistosomiasis is a global health disease, and Schistosome infection can lead to complications such as liver fibrosis and portal hypertension [133]. At present, the aptamer LC15 obtained from Schistosoma japonicum egg screening can be used as a specific tool for accurate diagnosis and targeted therapy. It can carry specific drugs to kill Schistosoma japonicum eggs and effectively improve the serious health problems caused by Schistosoma parasite infection [134].
Simulation of Aptamers and Targets
Aptamers enter cells by binding to protein targets on the cell surface and being internalized. Many targets have been identified, but how the target and aptamer interact is still not very clear, because the protein is difficult to isolate and purify, and even if isolated, it is difficult to maintain its original state [135]. Therefore, at present, the interaction of aptamers with their targets can only be inferred by calculating molecular simulation docking. This is generally done by constructing the secondary and tertiary structure of the aptamer, performing homology modeling of the corresponding target protein, and performing simulation docking on the Discovery Studio software to find possible modes of action according to the ranking of ZRANK scores [136]. Due to the secondary and tertiary structures of the aptamer fold, protein homology modeling differs from theory and is entirely computer simulated. Its authenticity has yet to be confirmed, but it can be used as a theoretical reference.
Secondary and Tertiary Structure Construction of Aptamer
Mfold web server (http://unafold.rna.albany.edu/?q=mfold) was used to predict and analyze the linear ssDNA aptamer secondary structure [137]. The optimal operating parameters are as follows: the folding temperature was controlled at 37℃, the ion conditions were Na+ 1.0 mM, Mg2+ 0.0 mM, the second-best percentage was 50%, the window parameters were default, and the maximum distance between paired bases was unrestricted by default. The aptamer structure with the smallest free energy, the smallest G value, was obtained. Select secondary structure Vienna format as a template to build the tertiary structure, in RNAcomposer (http://rnacomposer.ibch.poznan.pl/) generated in the tertiary structure, download to generate the tertiary structure of PDB format [138]. The nucleic acid sequence of the RNA tertiary structure was mutated using the biological software Discovery Studio to convert RNA into DNA sequence, and the structure was optimized [136, 137].
Target Protein Homology Modeling
In order to obtain information of each species-related genes in NCBI (https://www.ncbi.nlm.nih.gov/gene/) and to find the corresponding protein gene, the aptamer corresponding target protein was found. We chose homo sapiens (human) to find the amino acid sequence of the desired protein by the relationship between the corresponding gene and the protein. Amino acid sequence imports SWISS—MODEL (https://swissmodel.expasy.org/interactive) to carry on the homologous modeling, which can be directly chosen to establish a MODEL to get the corresponding protein template. To find out the optimal template search sequence, the most extensive coverage (generally more than 30%) and high matching degree should be used as a template. In Table 3, the GMQE, QMEAN, Seq identity, MolProbity Score, Ramachandran, Ramachandran Outliers, and solvation series parameters of the corresponding template are given, which are searched in the template to remove GP73 low credibility. Other validations were performed with high confidence, and the best homology template in PDB format was downloaded as the docking receptor.
Molecular Simulation Docking Between Ligand Receptors
Docking of nucleic acid aptamers and proteins was performed in Discovery Studio. The water molecules on the surface of the protein were first removed and re-hydrogenated and structurally optimized in chemistry as acceptors. Before docking with Dock Proteins (ZDOCK), you need to choose enough parameters, including selecting “Angular Step size” to be more extensive and detailed 6 instead of 15, selecting “Zrank” to be true, and selecting “Angular step size” to be more extensive and detailed 6 instead of 15. Select “Parallel Processing” to false, and ZDOCK runs. After completion of docking, the best docking result was selected according to the ZRANK scoring order [136]. By changing different docking methods, ZRANK scores of corresponding structural maps were obtained, and the interaction modes of aptamers and proteins were analyzed. Whether the motif of the aptamer binds to the target protein in a similar way to that of the contrast antibody is not known, nor is it clear that it is consistent with the results of computer simulations. In general, lower ZRANK scores indicate stronger receptor–ligand interactions [139]. The parameters and images corresponding to the docking results are shown in Table 4 and Fig. 2, respectively.
Discussion
Aptamers bind cells in an antibody-like manner, recognize cell-specific targets, enter the cell by endocytosis to form vesicles, and after entering the cell, some of the aptamers escape from the vesicles. Some aptamers function in the cytoplasm, while others enter the nucleus [140]. Since their discovery, aptamers have attracted much attention due to their non-toxicity, low immunogenicity, easy penetration of tissue barriers, and the advantages of multiple targets (amino acids, peptides, proteins [4, 10, 14], antibiotics [15], cells, viruses [20, 23], bacteria [24, 26]). At present, the defects of aptamer and SELEX technology hinder the utilization degree of aptamer. Improving the screening process and optimizing aptamer may make new breakthroughs in aptamer research [141]. Despite many setbacks in research, it has been used as a potential alternative to antibodies and diagnostic reagents in biomedical applications such as disease diagnosis, molecular imaging, drug delivery, biomarker discovery, and drug screening [142]. By summarizing the aptamers that have been patented so far, we get a general idea of the current state of research. Although many aptamers have been discovered, they are mostly used in other industries. In medicine, it is still in the stage of basic research, and there is still a gap between it and clinical diagnosis and treatment. In the process of screening aptamers, the biological characteristics such as specificity, affinity, stability, truncation and modification, carrying decoy ODN, micro-RNA or siRNA, etc., still need to be determined, which increases the cost of research and leads to the bottleneck of research. At present, the emergence of a variety of bioanalysis software provides convenience and support for related research. In addition to comparing with the existing experimental results, it can also provide certain guidance for the experiment.
Conclusion
The high affinity, targeting specificity, and cell internalization ability exhibited by aptamers are key to their application in drug delivery and the treatment of liver diseases. They can search for different target proteins and be applied to the diagnosis and treatment of liver diseases through screening corresponding aptamers.
Data Availability
The datasets analyzed during this study are available from the corresponding author on reasonable request.
References
Ellington, A. D., & Szostak, J. W. (1990). In vitro selection of RNA molecules that bind specific ligands. Nature, 346(6287), 818–822.
Tuerk, C., & Gold, L. (1990). Systematic evolution of ligands by exponential enrichment: RNA ligands to bacteriophage T4 DNA polymerase. Science (New York, N.Y.), 249(4968), 505–510.
Pal, S., Harmsen, S., Oseledchyk, A., Hsu, H. T., & Kircher, M. F. (2017). MUC1 aptamer targeted SERS nanoprobes. Advanced Functional Materials, 27(32), 1606632.
Ireson, C. R., & Kelland, L. R. (2006). Discovery and development of anticancer aptamers. Molecular Cancer Therapeutics, 5(12), 2957–2962.
Geiger, A., Burgstaller, P., von der Eltz, H., Roeder, A., & Famulok, M. (1996). RNA aptamers that bind l-arginine with sub-micromolar dissociation constants and high enantioselectivity. Nucleic Acids Research, 24(6), 1029–1036.
Mannironi, C., Scerch, C., Fruscoloni, P., & Tocchini-Valentini, G. P. (2000). Molecular recognition of amino acids by RNA aptamers: the evolution into an l-tyrosine binder of a dopamine-binding RNA motif. RNA (New York, N.Y.), 6(4), 520–527.
Harada, K., & Frankel, A. D. (1995). Identification of two novel arginine binding DNAs. The EMBO Journal, 14(23), 5798–5811.
Williams, K. P., Liu, X. H., Schumacher, T. N., Lin, H. Y., Ausiello, D. A., Kim, P. S., & Barte, D. P. (1997). Bioactive and nuclease-resistantl-DNA ligand of vasopressin. Proceedings of the National Academy of Sciences of the United States of America, 94(21), 11285–90.
Chen, H., McBroom, D. G., Zhu, Y. Q., Gold, L., & North, T. W. (1996). Inhibitory RNA ligand to reverse transcriptase from feline immunodeficiency virus. Biochemistry, 35(21), 6923–6930.
Dang, C., & Jayasena, S. D. (1996). Oligonucleotide inhibitors of Taq DNA polymerase facilitate detection of low copy number targets by PCR. Journal of Molecular Biology, 264(2), 268–278.
Jellinek, D., Green, L. S., Bell, C., Lynott, C. K., Gill, N., Vargeese, C., Kirschenheuter, G., McGee, D. P., Abesinghe, P., & Pieken, W. A. (1995). Potent 2′-amino-2′-deoxypyrimidine RNA inhibitors of basic fibroblast growth factor. Biochemistry, 34(36), 11363–11372.
Davis, K. A., Lin, Y., Abrams, B., & Jayasena, S. D. (1998). Staining of cell surface human CD4 with 2′-F-pyrimidine-containing RNA aptamers for flow cytometry. Nucleic Acids Research, 26(17), 3915–3924.
Mallikaratchy, P., Stahelin, R. V., Cao, Z., Cho, W., & Tan, W. (2006). Selection of DNA ligands for protein kinase C-delta. Chemical Communications (Cambridge, England), 30, 3229–3231.
Mendonsa, S. D., & Bowser, M. T. (2004). In vitro selection of high-affinity DNA ligands for human IgE using capillary electrophoresis. Analytical Chemistry, 76(18), 5387–5392.
Wallace, S. T., & Schroeder, R. (1998). In vitro selection and characterization of streptomycin-binding RNAs: recognition discrimination between antibiotics. RNA (New York, N.Y.), 4(1), 112–123.
Shangguan, D., Li, Y., Tang, Z., Cao, Z. C., Chen, H. W., Mallikaratchy, P., Sefah, K., Yang, C. J., & Tan, W. (2006). Aptamers evolved from live cells as effective molecular probes for cancer study. Proceedings of the National Academy of Sciences of the United States of America, 103(32), 11838–11843.
Tang, Z., Shangguan, D., Wang, K., Shi, H., Sefah, K., Mallikratchy, P., Chen, H. W., Li, Y., & Tan, W. (2007). Selection of aptamers for molecular recognition and characterization of cancer cells. Analytical Chemistry, 79(13), 4900–4907.
Chen, H. W., Medley, C. D., Sefah, K., Shangguan, D., Tang, Z., Meng, L., Smith, J. E., & Tan, W. (2008). Molecular recognition of small-cell lung cancer cells using aptamers. ChemMedChem, 3(6), 991–1001.
Sefah, K., Tang, Z. W., Shangguan, D. H., Chen, H., Lopez-Colon, D., Li, Y., Parekh, P., Martin, J., Meng, L., Phillips, J. A., Kim, Y. M., & Tan, W. H. (2009). Molecular recognition of acute myeloid leukemia using aptamers. Leukemia, 23(2), 235–244.
Pan, W., Craven, R. C., Qiu, Q., Wilson, C. B., Wills, J. W., Golovine, S., & Wang, J. F. (1995). Isolation of virus-neutralizing RNAs from a large pool of random sequences. Proceedings of the National Academy of Sciences of the United States of America, 92(25), 11509–11513.
Kumar, P. K., Machida, K., Urvil, P. T., Kakiuchi, N., Vishnuvardhan, D., Shimotohno, K., Taira, K., & Nishikawa, S. (1997). Isolation of RNA aptamers specific to the NS3 protein of hepatitis C virus from a pool of completely random RNA. Virology, 237(2), 270–282.
Gopinath, S. C. B., Misono, T. S., Kawasaki, K., Mizuno, T., Imai, M., Odagiri, T., & Kumar, P. K. R. (2006). An RNA aptamer that distinguishes between closely related human influenza viruses and inhibits haemagglutinin-mediated membrane fusion. The Journal of General Virology, 87(Pt 3), 479–487.
Tang, Z., Parekh, P., Turner, P., Moyer, R. W., & Tan, W. (2009). Generating aptamers for recognition of virus-infected cells. Clinical Chemistry, 55(4), 813–822.
Bruno, J. G., & Kiel, J. L. (1999). In vitro selection of DNA aptamers to anthrax spores with electrochemiluminescence detection. Biosensors & Bioelectronics, 14(5), 457–464.
Hamula, C. L., Zhang, H., Guan, L. L., Li, X. F., & Le, X. C. (2008). Selection of aptamers against live bacterial cells. Analytical Chemistry, 80(20), 7812–7819.
Rajendran, M., & Ellington, A. D. (2008). Selection of fluorescent aptamer beacons that light up in the presence of zinc. Analytical and Bioanalytical Chemistry, 390(4), 1067–1075.
Seki, E., & Brenner, D. A. (2015). Recent advancement of molecular mechanisms of liver fibrosis. Journal of Hepato-Biliary-Pancreatic Sciences, 22(7), 512–518.
Lim, T. S., & Kim, J. K. (2020). Is liver biopsy still useful in the era of non-invasive tests? Clinical and Molecular Hepatology, 26(3), 302–304.
Zhou, G., Da, W., Bae, S., Nguyen, R., Huo, X., Han, S., Zhang, Z., Hebbard, L., Duan, W., Eslam, M., Liddle, C., Yuen, L., Lam, V., Qiao, L., & George, J. (2021). An aptamer-based drug delivery agent (CD133-apt-Dox) selectively and effectively kills liver cancer stem-like cells. Cancer Letters, 501, 124–132.
Lai, W. Y., Wang, J. W., Huang, B. T., Lin, E. P., & Yang, P. C. (2019). A novel TNF-α-targeting aptamer for TNF-α-mediated acute lung injury and acute liver failure. Theranostics, 9(6), 1741–1751.
Takeda, A. L., Colquitt, J., Clegg, A. J., & Jones, J. (2007). Pegaptanib and ranibizumab for neovascular age-related macular degeneration: A systematic review. British Journal of Ophthalmology, 91(9), 1177–1182.
Bates, P. J., Laber, D. A., Miller, D. M., Thomas, S. D., & Trent, J. O. (2009). Discovery and development of the G-rich oligonucleotide AS1411 as a novel treatment for cancer. Experimental and molecular pathology, 86(3), 151–164.
Lincoff, A. M., Mehran, R., Povsic, T. J., Zelenkofske, S. L., Huang, Z., Armstrong, P. W., Steg, P. G., Bode, C., Cohen, M. G., Buller, C., Laanmets, P., Valgimigli, M., Marandi, T., Fridrich, V., Cantor, W. J., Merkely, B., Lopez-Sendon, J., Cornel, J. H., Kasprzak, J. D., … Investigators, R.E.G.U.L.A.T.E.-P.C.I. (2016). Effect of the REG1 anticoagulation system versus bivalirudin on outcomes after percutaneous coronary intervention (REGULATE-PCI): A randomised clinical trial. Lancet (London, England), 387(10016), 349–356.
Dehghani, S., Nosrati, R., Yousefi, M., Nezami, A., Soltani, F., Taghdisi, S. M., Abnous, K., Alibolandi, M., & Ramezani, M. (2018). Aptamer-based biosensors and nanosensors for the detection of vascular endothelial growth factor (VEGF): A review. Biosensors & Bioelectronics, 110, 23–37.
Zhang, Y., Lai, B. S., & Juhas, M. (2019). Recent advances in aptamer discovery and applications. Molecules (Basel, Switzerland), 24(5), 941.
Ng, E. W. M., & Adamis, A. P. (2006). Anti-VEGF aptamer (pegaptanib) therapy for ocular vascular diseases. Annals of the New York Academy of Sciences, 1082, 151–171.
Sefah, K., Shangguan, D., Xiong, X., O’Donoghue, M. B., & Tan, W. (2010). Development of DNA aptamers using cell-SELEX. Nature protocols, 5(6), 1169–1185.
Meek, K. N., Rangel, A. E., & Heemstra, J. M. (2016). Enhancing aptamer function and stability via in vitro selection using modified nucleic acids. Methods (San Diego, California), 106, 29–36.
Healy, J. M., Lewis, S. D., Kurz, M., Boomer, R. M., Thompson, K. M., Wilson, C., & McCauley, T. G. (2004). Pharmacokinetics and biodistribution of novel aptamer compositions. Pharmaceutical Research, 21(12), 2234–2246.
Lee, C. H., Lee, S. H., Kim, J. H., Noh, Y. H., Noh, G. J., & Lee, S. W. (2015). Pharmacokinetics of a cholesterol-conjugated aptamer against the hepatitis C Virus (HCV) NS5B protein. Molecular Therapy. Nucleic acids, 4(10), e254.
Heo, K., Min, S. W., Sung, H. J., Kim, H. G., Kim, H. J., Kim, Y. H., Choi, B. K., Han, S., Chung, S., Lee, E. S., Chung, J., & Kim, I. H. (2016). An aptamer-antibody complex (oligobody) as a novel delivery platform for targeted cancer therapies. Journal of Controlled Release, 10(229), 1–9.
Chen, L., Rashid, F., Shah, A., Awan, H. M., Wu, M., Liu, A., Wang, J., Zhu, T., Luo, Z., & Shan, G. (2015). The isolation of an RNA aptamer targeting to p53 protein with single amino acid mutation. Proceedings of the National Academy of Sciences of the United States of America, 112(32), 10002–10007.
Takahashi, M., Minakawa, N., & Matsuda, A. (2009). Synthesis and characterization of 2′-modified-4′-thioRNA: A comprehensive comparison of nuclease stability. Nucleic Acids Research, 37(4), 1353–1362.
Nimjee, S. M., White, R. R., Becker, R. C., & Sullenger, B. A. (2017). Aptamers as therapeutics. Annual Review of Pharmacology and Toxicology, 57, 61–79.
Wilner, S. E., Wengerter, B., Maier, K., de Lourdes Borba Magalhães, M., Del-Amo, D. S., Pai, S., Opazo, F., Rizzoli, S. O., Yan, A., & Levy, M. (2012). An RNA alternative to human transferrin: a new tool for targeting human cells. Molecular Therapy Nucleic Acids, 1(5), e21.
Jo, H., & Ban, C. (2016). Aptamer–nanoparticle complexes as powerful diagnostic and therapeutic tools. Experimental & Molecular Medicine, 48(5), e230.
Jaffe, G. J., Eliott, D., Wells, J. A., Prenner, J. L., Papp, A., & Patel, S. (2016). A phase 1 study of intravitreous E10030 in combination with ranibizumab in neovascular age-related macular degeneration. Ophthalmology, 123(1), 78–85.
Jaffe, G. J., Ciulla, T. A., Ciardella, A. P., Devin, F., Dugel, P. U., Eandi, C. M., Masonson, H., Monés, J., Pearlman, J. A., Quaranta-El Maftouhi, M., Ricci, F., Westby, K., & Patel, S. C. (2017). Dual antagonism of PDGF and VEGF in neovascular age-related macular degeneration: a phase IIb, multicenter, randomized controlled trial. Ophthalmology, 124(2), 224–234.
Shoval, A., Markus, A., Zhou, Z., Liu, X., Cazelles, R., Willner, I., & Mandel, Y. (2019). Anti-VEGF-aptamer modified c-dots-a hybrid nanocomposite for topical treatment of ocular vascular disorders. Small (Weinheim an der Bergstrasse, Germany), 15(40), e1902776.
Leung, E., & Landa, G. (2013). Update on current and future novel therapies for dry age-related macular degeneration. Expert Review of Clinical Pharmacology, 6(5), 565–579.
Vater, A., & Klussmann, S. (2015). Turning mirror-image oligonucleotides into drugs: The evolution of Spiegelmer(®) therapeutics. Drug Discovery Today, 20(1), 147–155.
Oberthür, D., Achenbach, J., Gabdulkhakov, A., Buchner, K., Maasch, C., Falke, S., Rehders, D., Klussmann, S., & Betzel, C. (2015). Crystal structure of a mirror-image l-RNA aptamer (Spiegelmer) in complex with the natural l-protein target CCL2. Nature Communications, 6, 6923.
Menne, J., Eulberg, D., Beyer, D., Baumann, M., Saudek, F., Valkusz, Z., Więcek, A., Haller, H., Emapticap Study Group. (2017). C-C motif-ligand 2 inhibition with emapticap pegol (NOX-E36) in type 2 diabetic patients with albuminuria. Nephrology Dialysis Transplantation, 32(2), 307–315.
Hoellenriegel, J., Zboralski, D., Maasch, C., Rosin, N. Y., Wierda, W. G., Keating, M. J., Kruschinski, A., & Burger, J. A. (2014). The Spiegelmer NOX-A12, a novel CXCL12 inhibitor, interferes with chronic lymphocytic leukemia cell motility and causes chemosensitization. Blood, 123(7), 1032–1039.
Waters, E. K., Genga, R. M., Schwartz, M. C., Nelson, J. A., Schaub, R. G., Olson, K. A., Kurz, J. C., & McGinness, K. E. (2011). Aptamer ARC19499 mediates a procoagulant hemostatic effect by inhibiting tissue factor pathway inhibitor. Blood, 117(20), 5514–5522.
Do, N. Q., Chung, W. J., Truong, T. H. A., Heddi, B., & Phan, A. T. (2017). G-quadruplex structure of an anti-proliferative DNA sequence. Nucleic Acids Research, 45(12), 7487–7493.
Lincoff, A.M., Mehran, R., Povsic, T.J., Zelenkofske, S.L., Huang, Z., Armstrong, P.W., Steg, P.G., Bode, C., Cohen, M.G., Buller, C., Laanmets, P., Valgimigli, M., Marandi, T., Fridrich, V., Cantor, W.J., Merkely, B., Lopez-Sendon, J., Cornel, J.H., Kasprzak, J.D., Aschermann, M., Guetta, V., Morais, J., Sinnaeve, P.R., Huber, K., Stables, R., Sellers, M.A., Borgman, M., Glenn, L., Levinson, A.I., Lopes, R.D., Hasselblad, V., Becker, R.C., Alexander, J. H., … REGULATE-PCI Investigators. (2016). Effect of the REG1 anticoagulation system versus bivalirudin on outcomes after percutaneous coronary intervention (REGULATE-PCI): A randomised clinical trial. Lancet (London, England), 387(10016), 349–356.
Chen, W. C., Voos, K. M., Josephson, C. D., & Li, R. (2019). Short-acting anti-VWF (von Willebrand Factor) aptamer improves the recovery, survival, and hemostatic functions of refrigerated platelets. Arteriosclerosis, Thrombosis, and Vascular Biology, 39(10), 2028–2037.
Guo, Y., Wang, Y., Li, S., Niu, L., Wei, D., & Zhang, S. (2017). DNA-spheres decorated with magnetic nanocomposites based on terminal transfer reactions for versatile target detection and cellular targeted drug delivery. Chemical Communications (Cambridge, England), 53(35), 4826–4829.
Zhu, G., & Chen, X. (2018). Aptamer-based targeted therapy. Advanced Drug Delivery Reviews, 134, 65–78.
Ng, E. W., Shima, D. T., Calias, P., Cunningham, E. T., Jr., Guyer, D. R., & Adamis, A. P. (2006). Pegaptanib, a targeted anti-VEGF aptamer for ocular vascular disease. Nature Reviews. Drug Discovery, 5(2), 123–132.
Kourlas, H., & Schiller, D. S. (2006). Pegaptanib sodium for the treatment of neovascular age-related macular degeneration: A review. Clinical Therapeutics, 28(1), 36–44.
Veritti, D., Sarao, V., & Lanzetta, P. (2012). Neovascular age-related macular degeneration. Ophthalmologica, 227(Suppl 1), 11–20.
Eyetech Study Group. (2002). Preclinical and phase 1A clinical evaluation of an anti-VEGF pegylated aptamer (EYE001) for the treatment of exudative age-related macular degeneration. Retina, 22(2), 143–152.
Zhou, J., & Rossi, J. (2017). Aptamers as targeted therapeutics: Current potential and challenges. Nature Reviews. Drug Discovery, 16(3), 181–202.
Ni, Z., & Hui, P. (2009). Emerging pharmacologic therapies for wet age-related macular degeneration. Ophthalmologica, 223(6), 401–410.
Schwoebel, F., van Eijk, L. T., Zboralski, D., Sell, S., Buchner, K., Maasch, C., Purschke, W. G., Humphrey, M., Zöllner, S., Eulberg, D., Morich, F., Pickkers, P., & Klussmann, S. (2013). The effects of the anti-hepcidin Spiegelmer NOX-H94 on inflammation-induced anemia in cynomolgus monkeys. Blood, 121(12), 2311–2315.
Steurer, M., Montillo, M., Scarfò, L., Mauro, F. R., Andel, J., Wildner, S., Trentin, L., Janssens, A., Burgstaller, S., Frömming, A., Dümmler, T., Riecke, K., Baumann, M., Beyer, D., Vauléon, S., Ghia, P., Foà, R., Caligaris-Cappio, F., & Gobbi, M. (2019). Olaptesed pegol (NOX-A12) with bendamustine and rituximab: A phase IIa study in patients with relapsed/refractory chronic lymphocytic leukemia. Haematologica, 104(10), 2053–2060.
Chang, J. Y., Chantrathammachart, P., Monroe, D. M., & Key, N. S. (2012). Studies on the mechanism of action of the aptamer BAX499, an inhibitor of tissue factor pathway inhibitor. Thrombosis Research, 130(3), e151–e157.
Bates, P. J., Reyes-Reyes, E. M., Malik, M. T., Murphy, E. M., O’Toole, M. G., & Trent, J. O. (2017). G-quadruplex oligonucleotide AS1411 as a cancer-targeting agent: Uses and mechanisms. Biochimica et Biophysica Acta. General Subjects, 1861(5 Pt B), 1414–1428.
Jilma-Stohlawetz, P., Gorczyca, M. E., Jilma, B., Siller-Matula, J., Gilbert, J. C., & Knöbl, P. (2011). Inhibition of von Willebrand factor by ARC1779 in patients with acute thrombotic thrombocytopenic purpura. Thrombosis and Haemostasis, 105(3), 545–552.
Colquitt, J. L., Jones, J., Tan, S. C., Takeda, A., Clegg, A. J., & Price, A. (2008). Ranibizumab and pegaptanib for the treatment of age-related macular degeneration: A systematic review and economic evaluation. Health Technology Assessment, 12(16) iii–iv, ix–201.
Wolowacz, S. E., Roskell, N., Kelly, S., Maciver, F. M., & Brand, C. S. (2007). Cost effectiveness of pegaptanib for the treatment of age-related macular degeneration in the UK. PharmacoEconomics, 25(10), 863–879.
Brown, G. C., Brown, M. M., Brown, H. C., Kindermann, S., & Sharma, S. (2007). A value-based medicine comparison of interventions for subfoveal neovascular macular degeneration. Ophthalmology, 114(6), 1170–1178.
Javitt, J. C., Zlateva, G. P., Earnshaw, S. R., Pleil, A. M., Graham, C. N., Brogan, A. J., Shah, S. N., & Adamis, A. P. (2008). Cost-effectiveness model for neovascular age-related macular degeneration: Comparing early and late treatment with pegaptanib sodium based on visual acuity. Value Health, 11(4), 563–574.
Zhou, J., & Rossi, J. J. (2014). Cell-type-specific, aptamer-functionalized agents for targeted disease therapy. Molecular Therapy. Nucleic Acids, 3(6), e169.
Castanotto, D., & Rossi, J. J. (2009). The promises and pitfalls of RNA-interference-based therapeutics. Nature, 457(7228), 426–433.
Sicco, E., Baez, J., Ibarra, M., Fernández, M., Cabral, P., Moreno, M., Cerecetto, H., & Calzada, V. (2020). Sgc8-c aptamer as a potential theranostic agent for hemato-oncological malignancies. Cancer Biotherapy & Radiopharmaceuticals, 35(4), 262–270.
Yan, A. C., & Levy, M. (2018). Aptamer-mediated delivery and cell-targeting aptamers: room for improvement. Nucleic Acid Therapeutics, 28(3), 194–199.
Luedde, T., Kaplowitz, N., & Schwabe, R. F. (2014). Cell death and cell death responses in liver disease: Mechanisms and clinical relevance. Gastroenterology, 147(4), 765–783.
Kew, M. C. (2000). Serum aminotransferase concentration as evidence of hepatocellular damage. Lancet (London, England), 355(9204), 591–592.
Chen, X., Pan, Y., Liu, H., Bai, X., Wang, N., & Zhang, B. (2016). Label-free detection of liver cancer cells by aptamer-based microcantilever biosensor. Biosensors & Bioelectronics, 15(79), 353–358.
Zhang, L., Wang, S., Yang, Z., Hoshika, S., Xie, S., Li, J., Chen, X., Wan, S., Li, L., Benner, S. A., & Tan, W. (2020). An aptamer-nanotrain assembled from six-letter DNA delivers doxorubicin selectively to liver cancer cells. Angewandte Chemie International Edition, 59(2), 663–668.
Guo, X., Huang, Z., Chen, J., He, K., Lin, J., Zhang, H., & Zeng, Y. (2022). Synergistic delivery of resveratrol and ultrasmall copper-based nanoparticles by aptamer-functionalized ultrasound nanobubbles for the treatment of nonalcoholic fatty liver disease. Frontiers in Physiology, 13, 950141.
Lai, Z., Tan, J., Wan, R., Tan, J., Zhang, Z., Hu, Z., Li, J., Yang, W., Wang, Y., Jiang, Y., He, J., Yang, N., Lu, X., & Zhao, Y. (2017). An ‘activatable’ aptamer-based fluorescence probe for the detection of HepG2 cells. Oncology Reports, 37(5), 2688–2694.
Hu, Z., Tan, J., Lai, Z., Zheng, R., Zhong, J., Wang, Y., Li, X., Yang, N., Li, J., Yang, W., Huang, Y., Zhao, Y., & Lu, X. (2017). Aptamer combined with fluorescent silica nanoparticles for detection of hepatoma cells. Nanoscale Research Letters, 12(1), 96.
Hu, Z., He, J., Gong, W., Zhou, N., Zhou, S., Lai, Z., Zheng, R., Wang, Y., Yang, X., Yang, W., Zhong, L., Lu, X., & Zhao, Y. (2018). TLS11a aptamer/CD3 antibody anti-tumor system for liver cancer. Journal of Biomedical Nanotechnology, 14(9), 1645–1653.
Wang, S., Zhang, C., Wang, G., Cheng, B., Wang, Y., Chen, F., Chen, Y., Feng, M., & Xiong, B. (2016). Aptamer-mediated transparent-biocompatible nanostructured surfaces for hepotocellular circulating tumor cells enrichment. Theranostics, 6(11), 1877–1886.
Joo, M., Baek, S. H., Cheon, S. A., Chun, H. S., Choi, S. W., & Park, T. J. (2017). Development of aflatoxin B(1) aptasensor based on wide-range fluorescence detection using graphene oxide quencher. Colloids and Surfaces B, Biointerfaces, 154, 27–32.
Kaur, H. (2019). Aptamer conjugated quantum dots for imaging cellular uptake in cancer cells. Journal of Nanoscience and Nanotechnology, 19(7), 3798–3803.
Zhou, Y., Li, W., Tseng, Y., Zhang, J., & Liu, J. (2019). Developing slow-off dickkopf-1 aptamers for early-diagnosis of hepatocellular carcinoma. Talanta, 194, 422–429.
Yan, H., Gao, X., Zhang, Y., Chang, W., Li, J., Li, X., Du, Q., & Li, C. (2018). Imaging tiny hepatic tumor xenografts via endoglin-targeted paramagnetic/optical nanoprobe. ACS Applied Materials & Interfaces, 10(20), 17047–17057.
Zhong, L., Zou, H., Huang, Y., Gong, W., He, J., Tan, J., Lai, Z., Li, Y., Zhou, C., Zhang, G., Li, G., Yang, N., & Zhao, Y. (2019). Magnetic endoglin aptamer nanoprobe for targeted diagnosis of solid tumor. Journal of Biomedical Nanotechnology, 15(2), 352–362.
Zhao, M., Dong, L., Liu, Z., Yang, S., Wu, W., & Lin, J. (2018). In vivo fluorescence imaging of hepatocellular carcinoma using a novel GPC3-specific aptamer probe. Quantitative Imaging in Medicine and Surgery, 8(2), 151–160.
Alshaer, W., Ababneh, N., Hatmal, M., Izmirli, H., Choukeife, M., Shraim, A., Sharar, N., Abu-Shiekah, A., Odeh, F., Al Bawab, A., Awidi, A., & Ismail, S. (2017). Selection and targeting of EpCAM protein by ssDNA aptamer. PLoS ONE, 12(12), e189558.
Liu, Z., Sun, X., Xiao, S., Lin, Y., Li, C., Hao, N., Zhou, M., Deng, R., Ke, S., & Zhong, Z. (2018). Characterization of aptamer-mediated gene delivery system for liver cancer therapy. Oncotarget, 9(6), 6830–6840.
Liu, Y., Wu, X., Gao, Y., Zhang, J., Zhang, D., Gu, S., Zhu, G., Liu, G., & Li, X. (2016). Aptamer-functionalized peptide H3CR5C as a novel nanovehicle for codelivery of fasudil and miRNA-195 targeting hepatocellular carcinoma. International Journal of Nanomedicine, 11, 3891–3905.
Qu, L., Xu, J., Tan, X., Liu, Z., Xu, L., & Peng, R. (2014). Dual-aptamer modification generates a unique interface for highly sensitive and specific electrochemical detection of tumor cells. ACS Applied Materials & Interfaces, 6(10), 7309–7315.
Dong, L., Tan, Q., Ye, W., Liu, D., Chen, H., Hu, H., Wen, D., Liu, Y., Cao, Y., Kang, J., Fan, J., Guo, W., & Wu, W. (2015). Screening and identifying a novel ssDNA aptamer against alpha-fetoprotein using CE-SELEX. Scientific Reports, 5, 15552.
Duo, J., Chiriac, C., Huang, R. Y., Mehl, J., Chen, G., Tymiak, A., Sabbatini, P., Pillutla, R., & Zhang, Y. (2018). Slow off-rate modified aptamer (SOMAmer) as a novel reagent in immunoassay development for accurate soluble glypican-3 quantification in clinical samples. Analytical Chemistry, 90(8), 5162–5170.
Cho, Y., Lee, Y. B., Lee, J. H., Lee, D. H., Cho, E. J., Yu, S. J., Kim, Y. J., Kim, J. I., Im, J. H., Lee, J. H., Oh, E. J., & Yoon, J. H. (2016). Modified AS1411 Aptamer suppresses hepatocellular carcinoma by up-regulating galectin-14. PLoS ONE, 11(8), e160822.
Trinh, T. L., Zhu, G., Xiao, X., Puszyk, W., Sefah, K., Wu, Q., Tan, W., & Liu, C. (2015). A synthetic aptamer-drug adduct for targeted liver cancer therapy. PLoS ONE, 10(11), e136673.
Scaggiante, B., Farra, R., Dapas, B., Baj, G., Pozzato, G., Grassi, M., Zanconati, F., & Grassi, G. (2016). Aptamer targeting of the elongation factor 1A impairs hepatocarcinoma cells viability and potentiates bortezomib and idarubicin effects. International Journal of Pharmaceutics, 506(1–2), 268–279.
Lee, K. A., Ahn, J. Y., Lee, S. H., Singh Sekhon, S., Kim, D. G., Min, J., & Kim, Y. H. (2015). Aptamer-based sandwich assay and its clinical outlooks for detecting lipocalin-2 in hepatocellular carcinoma (HCC). Scientific Reports, 5, 10897.
Bhattacharya, S. D., Mi, Z., Kim, V. M., Guo, H., Talbot, L. J., & Kuo, P. C. (2012). Osteopontin regulates epithelial mesenchymal transition-associated growth of hepatocellular cancer in a mouse xenograft model. Annals of Surgery, 255(2), 319–325.
Wang, T., Rahimizadeh, K., & Veedu, R. N. (2020). Development of a novel DNA oligonucleotide targeting low-density lipoprotein receptor. Molecular Therapy. Nucleic Acids, 19, 190–198.
Wang, T., Philippovich, S., Mao, J., & Veedu, R. N. (2019). Efficient epidermal growth factor receptor targeting oligonucleotide as a potential molecule for targeted cancer therapy. International Journal of Molecular Sciences, 20(19), 4700.
Rong, Y., Chen, H., Zhou, X. F., Yin, C. Q., Wang, B. C., Peng, C. W., Liu, S. P., & Wang, F. B. (2016). Identification of an aptamer through whole cell-SELEX for targeting high metastatic liver cancers. Oncotarget, 7(7), 8282–8294.
Hwang, J., Seo, Y., Jo, Y., Son, J., & Choi, J. (2016). Aptamer-conjugated live human immune cell based biosensors for the accurate detection of C-reactive protein. Scientific Reports, 6, 34778.
Kang, J., Lee, M. S., Copland, J. A., 3rd., Luxon, B. A., & Gorenstein, D. G. (2008). Combinatorial selection of a single stranded DNA thioaptamer targeting TGF-beta1 protein. Bioorganic & Medicinal Chemistry Letters, 18(6), 1835–1839.
Chen, Z., Liu, H., Jain, A., Zhang, L., Liu, C., & Cheng, K. (2017). Discovery of aptamer ligands for hepatic stellate cells using SELEX. Theranostics, 7(12), 2982–2995.
Xi, Z., Gong, Q., Wang, C., & Zheng, B. (2018). Highly sensitive chemiluminescent aptasensor for detecting HBV infection based on rapid magnetic separation and double-functionalized gold nanoparticles. Scientific Reports, 8(1), 9444.
Gao, Y., Yu, X., Xue, B., Zhou, F., Wang, X., Yang, D., Liu, N., Xu, L., Fang, X., & Zhu, H. (2014). Inhibition of hepatitis C virus infection by DNA aptamer against NS2 protein. PLoS ONE, 9(2), e90333.
Lee, C. H., Lee, Y. J., Kim, J. H., Lim, J. H., Kim, J. H., Han, W., Lee, S. H., Noh, G. J., & Lee, S. W. (2013). Inhibition of hepatitis C virus (HCV) replication by specific RNA aptamers against HCV NS5B RNA replicase. Journal of Virology, 87(12), 7064–7074.
Nakamura, N., Matsui, T., Ishibashi, Y., Sotokawauchi, A., Fukami, K., Higashimoto, Y., & Yamagishi, S. I. (2017). RAGE-aptamer attenuates the growth and liver metastasis of malignant melanoma in nude mice. Molecular Medicine (Cambridge, Massachusetts), 23, 295–306.
Zhang, G. Q., Zhong, L. P., Yang, N., & Zhao, Y. X. (2019). Screening of aptamers and their potential application in targeted diagnosis and therapy of liver cancer. World Journal of Gastroenterology, 25(26), 3359–3369.
Forner, A., Llovet, J. M., & Bruix, J. (2012). Hepatocellular carcinoma. Lancet (London, England), 379(9822), 1245–1255.
Sun, J. H., Luo, Q., Liu, L. L., & Song, G. B. (2016). Liver cancer stem cell markers: progression and therapeutic implications. World Journal of Gastroenterology, 22(13), 3547–3557.
Sigismund, S., Avanzato, D., & Lanzetti, L. (2018). Emerging functions of the EGFR in cancer. Molecular Oncology, 12(1), 3–20.
Campana, L., & Iredale, J. P. (2017). Regression of liver fibrosis. Seminars in Liver Disease, 37(1), 1–10.
Hernandez-Gea, V., & Friedman, S. L. (2011). Pathogenesis of liver fibrosis. Annual Review of Pathology, 6, 425–456.
Sun, M., & Kisseleva, T. (2015). Reversibility of liver fibrosis. Clinics and Research in Hepatology and Gastroenterology, 39(Suppl 1), S60–S63.
Omar, R., Yang, J., Liu, H., Davies, N. M., & Gong, Y. (2016). Hepatic stellate cells in liver fibrosis and siRNA-based therapy. Reviews of Physiology, Biochemistry and Pharmacology, 172, 1–37.
Cequera, A., de León, G., & Méndez, M. C. (2014). Biomarcadores para fibrosis hepática, avances, ventajas y desventajas [Biomarkers for liver fibrosis: Advances, advantages and disadvantages]. Revista de Gastroenterologia de Mexico, 79(3), 187–199.
Koch, A., Trautwein, C., & Tacke, F. (2017). Acute liver failure. Medizinische Klinik, Intensivmedizin und Notfallmedizin, 112(4), 371–381.
Orava, E. W., Jarvik, N., Shek, Y. L., Sidhu, S. S., & Gariépy, J. (2013). A short DNA aptamer that recognizes TNFα and blocks its activity in vitro. ACS Chemical Biology, 8(1), 170–178.
Zhang, S., Hu, B., Xu, J., Ren, Q., Wang, L., & Wang, S. (2019). Influenza A virus infection induces liver injury in mice. Microbial Pathogenesis, 137, 103736.
Fan, Z., Chen, L., Li, J., Cheng, X., Yang, J., Tian, C., Zhang, Y., Huang, S., Liu, Z., & Cheng, J. (2020). Clinical Features of COVID-19-Related Liver Functional Abnormality. Clinical Gastroenterology and Hepatology : The Official Clinical Practice Journal of the American Gastroenterological Association, 18(7), 1561–1566.
Seto, W. K., Lo, Y. R., Pawlotsky, J. M., & Yuen, M. F. (2018). Chronic hepatitis B virus infection. Lancet (London, England), 392(10161), 2313–2324.
Clark, A. M., Ma, B., Taylor, D. L., Griffith, L., & Wells, A. (2016). Liver metastases: Microenvironments and ex-vivo models. Experimental Biology and Medicine (Maywood, N.J.), 241(15), 1639–1652.
Takahara, T., Xue, F., Mazzone, M., Yata, Y., Nonome, K., Kanayama, M., Kawai, K., Pisacane, A. M., Takahara, S., Li, X. K., Comoglio, P. M., Sugiyama, T., & Michieli, P. (2008). Metron factor-1 prevents liver injury without promoting tumor growth and metastasis. Hepatology, 47(6), 2010–2025.
Brodt, P. (2016). Role of the microenvironment in liver metastasis: from pre- to prometastatic niches. Clinical Cancer Research: An Official Journal of the American Association for Cancer Research, 22(24), 5971–5982.
Gong, W., Huang, F., Sun, L., Yu, A., Zhang, X., Xu, Y., Shen, Y., & Cao, J. (2018). Toll-like receptor-2 regulates macrophage polarization induced by excretory-secretory antigens from Schistosoma japonicum eggs and promotes liver pathology in murine schistosomiasis. PLoS Neglected Tropical Diseases, 12(12), e7000.
Long, Y., Qin, Z., Duan, M., Li, S., Wu, X., Lin, W., Li, J., Zhao, Z., Liu, J., Xiong, D., Huang, Y., Hu, X., Yang, C., Ye, M., & Tan, W. (2016). Screening and identification of DNA aptamers toward Schistosoma japonicum eggs via SELEX. Scientific Reports, 6, 24986.
Alberti, S., Saha, S., Woodruff, J. B., Franzmann, T. M., Wang, J., & Hyman, A. A. (2018). A user’s guide for phase separation assays with purified proteins. Journal of Molecular Biology, 430(23), 4806–4820.
Hsieh, P. C., Lin, H. T., Chen, W. Y., Tsai, J. J. P., & Hu, W. P. (2017). The Combination of computational and biosensing technologies for selecting aptamer against prostate specific antigen. BioMed Research International, 2017, 5041683.
Heiat, M., Najafi, A., Ranjbar, R., Latifi, A. M., & Rasaee, M. J. (2016). Computational approach to analyze isolated ssDNA aptamers against angiotensin II. Journal of Biotechnology, 230, 34–39.
Popenda, M., Szachniuk, M., Antczak, M., Purzycka, K. J., Lukasiak, P., Bartol, N., Blazewicz, J., & Adamiak, R. W. (2012). Automated 3D structure composition for large RNAs. Nucleic Acids Research, 40(14), e112.
Hu, W. P., Kumar, J. V., Huang, C. J., & Chen, W. Y. (2015). Computational selection of RNA aptamer against angiopoietin-2 and experimental evaluation. BioMed Research International, 2015, 658712.
Wan, L. Y., Yuan, W. F., Ai, W. B., Ai, Y. W., Wang, J. J., Chu, L. Y., Zhang, Y. Q., & Wu, J. F. (2019). An exploration of aptamer internalization mechanisms and their applications in drug delivery. Expert Opinion on Drug Delivery, 16(3), 207–218.
Sun, H., & Zu, Y. (2015). A highlight of recent advances in aptamer technology and its application. Molecules (Basel, Switzerland), 20(7), 11959–11980.
Gotrik, M. R., Feagin, T. A., Csordas, A. T., Nakamoto, M. A., & Soh, H. T. (2016). Advancements in aptamer discovery technologies. Accounts of Chemical Research, 49(9), 1903–1910.
Funding
This study was supported by Nature Science Foundation of Hubei Province (Grant No. 2021CFB537) and Open Foundation of Hubei Province Key Laboratory of Tumor Microenvironment and Immunotherapy (Grant No. 2023KZL018).
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Xu, C., Tan, Y., Zhang, LY. et al. The Application of Aptamer and Research Progress in Liver Disease. Mol Biotechnol 66, 1000–1018 (2024). https://doi.org/10.1007/s12033-023-01030-4
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DOI: https://doi.org/10.1007/s12033-023-01030-4