Exploration of Targeted Anti-tumor Therapy

Table 1. Strengths and weaknesses of aptamers in comparison with antibodies

Criteria	Aptamers	Antibodies
Size	5–15 kDa	150–180 kDa
• Target accessibility	High	Low
• Minimal target size	60 Da	600 Da
• Tissue/tumor penetration	High	Low
• Clearance rate	Rapid	Slow
Basic composition	Nucleotides	Amino acids
• Resistance to harsh environment conditions (pH and temperature)	High	Low
• Shelf-life	Long	Limited
• Versatility to chemical	High	Limited
• Nuclease degradation	Sensitive; limited half-life in vivo (unmodified)	Resistant; long half-life in vivo
Therapeutic efficacy
• Affinity and specificity	K_D, nano/pico	K_D, nano/pico
• Immunogenicity	Low/none	High
• Modulation of target activity	Yes	Yes
• Fc-mediated effector	No	Yes
Discovery
• Time	In vitro SELEX, 2–8 weeks	In vivo biological process, 6
Production
• Scale up	Easy	Hard
• Batch to batch variation	None	High

Return to article view

K_D values: dissociation constants

Declarations

Author contributions

Conceptualization: LC; writing-original draft preparation: LC; writing-review and editing: LA, SC, MF, LC. All the authors gave final approval of the version to be published.

Conflicts of interest

The authors declare that they have no conflicts of interest.

Ethical approval

Not applicable.

Consent to participate

Not applicable.

Consent to publication

Not applicable.

Availability of data and materials

Not applicable.

Funding

This work was supported by Fondazione AIRC per la Ricerca sul Cancro (IG 23052) to LC. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Copyright

References

Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68:394–424. [DOI] [PubMed]

Falzone L, Salomone S, Libra M. Evolution of cancer pharmacological treatments at the turn of the third millennium. Front Pharmacol. 2018;9:1300. [DOI] [PubMed] [PMC]

Holohan C, Van Schaeybroeck S, Longley DB, Johnston PG. Cancer drug resistance: an evolving paradigm. Nat Rev Cancer. 2013;13:714–26. [DOI] [PubMed]

Xu G, McLeod HL. Strategies for enzyme/prodrug cancer therapy. Clin Cancer Res. 2001;7:3314–24. [PubMed]

Cree IA, Charlton P. Molecular chess? Hallmarks of anti-cancer drug resistance. BMC Cancer. 2017;17:10. [DOI] [PubMed] [PMC]

D’Alterio C, Scala S, Sozzi G, Roz L, Bertolini G. Paradoxical effects of chemotherapy on tumor relapse and metastasis promotion. Semin Cancer Biol. 2020;60:351–61. [DOI] [PubMed]

Madden EC, Gorman AM, Logue SE, Samali A. Tumour cell secretome in chemoresistance and tumour recurrence. Trends Cancer. 2020;6:489–505. [DOI] [PubMed]

Colton M, Cheadle EJ, Honeychurch J, Illidge TM. Reprogramming the tumour microenvironment by radiotherapy: implications for radiotherapy and immunotherapy combinations. Radiat Oncol. 2020;15:254. [DOI] [PubMed] [PMC]

Hirata E, Sahai E. Tumor microenvironment and differential responses to therapy. Cold Spring Harb Perspect Med. 2017;7:a026781. [DOI] [PubMed] [PMC]

10.

Baudino TA. Targeted cancer therapy: the next generation of cancer treatment. Curr Drug Discov Technol. 2015;12:3–20. [DOI] [PubMed]

11.

Imai K, Takaoka A. Comparing antibody and small-molecule therapies for cancer. Nat Rev Cancer. 2006;6:714–27. [DOI] [PubMed]

12.

Aggarwal S. Targeted cancer therapies. Nat Rev Drug Discov. 2010;9:427–8. [DOI] [PubMed]

13.

Wang W, Sun Q. Novel targeted drugs approved by the NMPA and FDA in 2019. Signal Transduct Target Ther. 2020;5:65. [DOI] [PubMed] [PMC]

14.

Seebacher NA, Stacy AE, Porter GM, Merlot AM. Clinical development of targeted and immune based anti-cancer therapies. J Exp Clin Cancer Res. 2019 11.;38:156. [DOI] [PubMed] [PMC]

15.

Oh DY, Bang YJ. HER2-targeted therapies-a role beyond breast cancer. Nat Rev Clin Oncol. 2020;17:33–48. [DOI] [PubMed]

16.

Doroshow JH, Simon RM. On the design of combination cancer therapy. Cell. 2017;171:1476–8. [DOI] [PubMed] [PMC]

17.

Bayat Mokhtari R, Homayouni TS, Baluch N, Morgatskaya E, Kumar S, Das B, et al. Combination therapy in combating cancer. Oncotarget. 2017;8:38022–43. [DOI] [PubMed] [PMC]

18.

Bianchini G, Balko JM, Mayer IA, Sanders ME, Gianni L. Triple-negative breast cancer: challenges and opportunities of a heterogeneous disease. Nat Rev Clin Oncol 2016;3:674–90. [DOI]

19.

Qazi MA, Vora P, Venugopal C, Sidhu SS, Moffat J, Swanton C, et al. Intratumoral heterogeneity: pathways to treatment resistance and relapse in human glioblastoma. Ann Oncol. 2017;28:1448–56. [DOI] [PubMed]

20.

Sun H, Zhu X, Lu PY, Rosato RR, Tan W, Zu Y. Oligonucleotide aptamers: new tools for targeted cancer therapy. Mol Ther Nucleic Acids. 2014;3:e182. [DOI] [PubMed] [PMC]

21.

Cerchia L. Aptamers: promising tools for cancer diagnosis and therapy. Cancers (Basel). 2018;10:132. [DOI]

22.

Zhou J, Rossi J. Aptamers as targeted therapeutics: current potential and challenges. Nat Rev Drug Discov. 2017;16:181–202. [DOI] [PubMed] [PMC]

23.

Blind M, Blank M. Aptamer selection technology and recent advances. Mol Ther Nucleic Acids. 2015;4:e223. [DOI] [PubMed] [PMC]

24.

Kinghorn AB, Fraser LA, Lang S, Shiu SCC, Tanner JA. Aptamer bioinformatics. Int J Mol Sci. 2017;18:2516. [DOI]

25.

Tuerk C, Gold L. Systematic evolution of ligands by exponential enrichment: RNA ligands to bacteriophage T4 DNA polymerase. Science. 1990;249:505–10. [DOI] [PubMed]

26.

Ellington AD, Szostak JW. In vitro selection of RNA molecules that bind specific ligands. Nature. 1990;346:818–22. [DOI] [PubMed]

27.

Robertson DL, Joyce GF. Selection in vitro of an RNA enzyme that specifically cleaves single-stranded DNA. Nature. 1990;344:467–8. [DOI] [PubMed]

28.

Li L, Xu S, Yan H, Li X, Yazd HS, Li X, et al. Nucleic acid aptamers for molecular diagnostics and therapeutics: advances and perspectives. Angew Chem Int Ed Engl. 2020;60:2221–31. [DOI] [PubMed]

29.

Wang B. A new design for the fixed primer regions in an oligonucleotide library for SELEX aptamer screening. Front Chem. 2020;8:475. [DOI] [PubMed] [PMC]

30.

Kimoto M, Yamashige R, Matsunaga K, Yokoyama S, Hirao I. Generation of high-affinity DNA aptamers using an expanded genetic alphabet. Nat Biotechnol. 2013;31:453–7. [DOI] [PubMed]

31.

Ozer A, Pagano JM, Lis JT. New technologies provide quantum changes in the scale, speed, and success of SELEX methods and aptamer characterization. Mol Ther Nucleic Acids. 2014;3:e183. [DOI] [PubMed] [PMC]

32.

Liu Y, Kuan CT, Mi J, Zhang X, Clary BM, Bigner DD, et al. Aptamers selected against the unglycosylated EGFRvIII ectodomain and delivered intracellularly reduce membrane-bound EGFRvIII and induce apoptosis. Biol Chem. 2009;390:137–44. [DOI] [PubMed] [PMC]

33.

Shangguan D, Bing T, Zhang N. Cell-SELEX: aptamer selection against whole cells. In: Tan W, Fang X, editor. Aptamers selected by cell-SELEX for theranostics. Berlin: Springer; 20. pp. 13–33.

34.

Fechter P, Cruz Da Silva E, Mercier MC, Noulet F, Etienne-Seloum N, Guenot D, et al. RNA aptamers targeting integrin α5β1 as probes for cyto- and histo-fluorescence in glioblastoma. Mol Ther Nucleic Acids. 2019;17:63–77. [DOI] [PubMed] [PMC]

35.

Hicke BJ, Marion C, Chang YF, Gould T, Lynott CK, Parma D, et al. Tenascin-C aptamers are generated using tumor cells and purified protein. J Biol Chem. 2001;276:48644–54. [DOI] [PubMed]

36.

Tang Z, Shangguan D, Wang K, Shi H, Sefah K, Mallikratchy P, et al. Selection of aptamers for molecular recognition and characterization of cancer cells. Anal Chem. 2007;79:4900–7. [DOI] [PubMed]

37.

Camorani S, Esposito CL, Rienzo A, Catuogno S, Iaboni M, Condorelli G, et al. Inhibition of receptor signaling and of glioblastoma-derived tumor growth by a novel PDGFRβ aptamer. Mol Ther. 2014;22:828–41. [DOI] [PubMed] [PMC]

38.

Sefah K, Tang ZW, Shangguan DH, Chen H, Lopez-Colon D, Li Y, et al. Molecular recognition of acute myeloid leukemia using aptamers. Leukemia. 2009;23:235–44. [DOI] [PubMed] [PMC]

39.

Chen HW, Medley CD, Sefah K, Shangguan D, Tang Z, Meng L, et al. Molecular recognition of small-cell lung cancer cells using aptamers. ChemMedChem. 2008;3:991–1001. [DOI] [PubMed] [PMC]

40.

Shangguan D, Li Y, Tang Z, Cao ZC, Chen HW, Mallikaratchy P, et al. Aptamers evolved from live cells as effective molecular probes for cancer study. Proc Natl Acad Sci U S A. 2006;103:11838–43. [DOI] [PubMed] [PMC]

41.

Esposito CL, Passaro D, Longobardo I, Condorelli G, Marotta P, Affuso A, et al. A neutralizing RNA aptamer against EGFR causes selective apoptotic cell death. PLoS One. 2011;6:e24071. [DOI] [PubMed] [PMC]

42.

Li X, Zhang W, Liu L, Zhu Z, Ouyang G, An Y, et al. In vitro selection of DNA aptamers for metastatic breast cancer cell recognition and tissue imaging. Anal Chem. 2014;86:6596–603. [DOI] [PubMed]

43.

Liu M, Wang Z, Tan T, Chen Z, Mou X, Yu X, et al. An aptamer-based probe for molecular subtyping of breast cancer. Theranostics. 2018;8:5772–83. [DOI] [PubMed] [PMC]

44.

Camorani S, Granata I, Collina F, Leonetti F, Cantile M, Botti G, et al. Novel aptamers selected on living cells for specific recognition of triple-negative breast cancer. iScience. 2020;23:100979. [DOI] [PubMed] [PMC]

45.

Souza AG, Marangoni K, Fujimura PT, Alves PT, Silva MJ, Bastos VA, et al. 3D cell-SELEX: development of RNA aptamers as molecular probes for PC-3 tumor cell line. Exp Cell Res. 2016;341:147–56. [DOI] [PubMed]

46.

Zhong W, Pu Y, Tan W, Liu J, Liao J, Liu B, et al. Identification and application of an aptamer targeting papillary thyroid carcinoma using tissue-SELEX. Anal Chem. 2019;91:8289–97. [DOI] [PubMed]

47.

Sola M, Menon AP, Moreno B, Meraviglia-Crivelli D, Soldevilla MM, Cartón-García F, et al. Aptamers against live targets: is in vivo SELEX finally coming to the edge? Mol Ther Nucleic Acids. 2020;21:192–204. [DOI] [PubMed] [PMC]

48.

Mi J, Liu Y, Rabbani ZN, Yang Z, Urban JH, Sullenger BA, et al. In vivo selection of tumor-targeting RNA motifs. Nat Chem Biol. 2010;6:22–4. [DOI] [PubMed] [PMC]

49.

Cheng C, Chen YH, Lennox KA, Behlke MA, Davidson BL. In vivo SELEX for identification of brain-penetrating aptamers. Mol Ther Nucleic Acids. 2013;2:e67. [DOI] [PubMed] [PMC]

50.

Gelinas AD, Davies DR, Janjic N. Embracing proteins: structural themes in aptamer-protein complexes. Curr Opin Struct Biol. 2016;36:122–32. [DOI] [PubMed]

51.

Diafa S, Hollenstein M. Generation of aptamers with an expanded chemical repertoire. Molecules. 2015;20:16643–71. [DOI] [PubMed] [PMC]

52.

Da Pieve C, Blackshaw E, Missailidis S, Perkins AC. PEGylation and biodistribution of an anti-MUC1 aptamer in MCF-7 tumor-bearing mice. Bioconjug Chem. 2012;23:1377–81. [DOI] [PubMed]

53.

Heo K, Min SW, Sung HJ, Kim HG, Kim HJ, Kim YH, et al. An aptamer-antibody complex (oligobody) as a novel delivery platform for targeted cancer therapies. J Control Release. 2016;229:1–9. [DOI] [PubMed]

54.

Zhou F, Fu T, Huang Q, Kuai H, Mo L, Liu H, et al. Hypoxia-activated PEGylated conditional aptamer/ antibody for cancer imaging with improved specificity. J Am Chem Soc. 2019;141:18421–7. [DOI] [PubMed]

55.

Dassie JP, Giangrande PH. Current progress on aptamer-targeted oligonucleotide therapeutics. Ther Deliv. 2013;4:1527–46. [DOI] [PubMed] [PMC]

56.

Camorani S, Crescenzi E, Fedele M, Cerchia L. Oligonucleotide aptamers against tyrosine kinase receptors: prospect for anticancer applications. Biochim Biophys Acta Rev Cancer. 2018;1869:263–77. [DOI] [PubMed]

57.

Cerchia L, Esposito CL, Camorani S, Rienzo A, Stasio L, Insabato L, et al. Targeting Axl with an high-affinity inhibitory aptamer. Mol Ther. 2012;20:2291–303. [DOI] [PubMed] [PMC]

58.

Camorani S, Crescenzi E, Colecchia D, Carpentieri A, Amoresano A, Fedele M, et al. Aptamer targeting EGFRvIII mutant hampers its constitutive autophosphorylation and affects migration, invasion and proliferation of glioblastoma cells. Oncotarget. 2015;6:37570–87. [DOI] [PubMed] [PMC]

59.

Camorani S, Crescenzi E, Gramanzini M, Fedele M, Zannetti A, Cerchia L. Aptamer-mediated impairment of EGFR-integrin αvβ3 complex inhibits vasculogenic mimicry and growth of triple-negative breast cancers. Sci Rep. 2017;7:46659. [DOI] [PubMed] [PMC]

60.

Ueki R, Sando S. A DNA aptamer to c-Met inhibits cancer cell migration. Chem Commun (Camb). 2014;50:13131–4. [DOI] [PubMed]

61.

Camorani S, Fedele M, Zannetti A, Cerchia L. TNBC challenge: oligonucleotide aptamers for new imaging and therapy modalities. Pharmaceuticals (Basel). 2018;11:123. [DOI]

62.

McNamara JO, Kolonias D, Pastor F, Mittler RS, Chen L, Giangrande PH, et al. Multivalent 4-1BB binding aptamers costimulate CD8⁺ T cells and inhibit tumor growth in mice. J Clin Invest. 2008;118:376–86. [DOI] [PubMed] [PMC]

63.

Ueki R, Ueki A, Kanda N, Sando S. Oligonucleotide-based mimetics of hepatocyte growth factor. Angew Chem Int Ed Engl. 2016;55:579–82. [DOI] [PubMed]

64.

Mahlknecht G, Maron R, Mancini M, Schechter B, Sela M, Yarden Y. Aptamer to ErbB-2/HER2 enhances degradation of the target and inhibits tumorigenic growth. Proc Natl Acad Sci U S A. 2013;110:8170–5. [DOI] [PubMed] [PMC]

65.

Yang S, Wen J, Li H, Xu L, Liu Y, Zhao N, et al. Aptamer-engineered natural killer cells for cell-specific adaptive immunotherapy. Small. 2019;15:e1900903. [DOI] [PubMed] [PMC]

66.

Yoon S, Rossi JJ. Aptamers: uptake mechanisms and intracellular applications. Adv Drug Deliv Rev. 2018;134:22–35. [DOI] [PubMed] [PMC]

67.

Powell Gray B, Kelly L, Ahrens DP, Barry AP, Kratschmer C, Levy M, et al. Tunable cytotoxic aptamer-drug conjugates for the treatment of prostate cancer. Proc Natl Acad Sci U S A. 2018;115:4761–6. [DOI] [PubMed] [PMC]

68.

Chu TC, Marks JW 3rd, Lavery LA, Faulkner S, Rosenblum MG, Ellington AD, et al. Aptamer: toxin conjugates that specifically target prostate tumor cells. Cancer Res. 2006;66:5989–92. [DOI] [PubMed]

69.

Castanotto D, Rossi JJ. The promises and pitfalls of RNA-interference-based therapeutics. Nature. 2009;457:426–33. [DOI] [PubMed] [PMC]

70.

Porciani D, Cardwell LN, Tawiah KD, Alam KK, Lange MJ, Daniels MA, et al. Modular cell-internalizing aptamer nanostructure enables targeted delivery of large functional RNAs in cancer cell lines. Nat Commun. 2018;9:2283. [DOI] [PubMed] [PMC]

71.

Deeken JF, Löscher W. The blood-brain barrier and cancer: transporters, treatment, and Trojan horses. Clin Cancer Res. 2007;13:1663–74. [DOI] [PubMed]

72.

Macdonald J, Denoyer D, Henri J, Jamieson A, Burvenich IJG, Pouliot N, et al. Bifunctional aptamer-doxorubicin conjugate crosses the blood-brain barrier and selectively delivers its payload to EpCAM-positive tumor cells. Nucleic Acid Ther. 2020;30:117–28. [DOI] [PubMed] [PMC]

73.

Camorani S, Hill BS, Fontanella R, Greco A, Gramanzini M, Auletta L, et al. Inhibition of bone marrow-derived mesenchymal stem cells homing towards triple-negative breast cancer microenvironment using an anti-PDGFRβ aptamer. Theranostics. 2017;7:3595–607. [DOI] [PubMed] [PMC]

74.

Monaco I, Camorani S, Colecchia D, Locatelli E, Calandro P, Oudin A, et al. Aptamer functionalization of nanosystems for glioblastoma targeting through the blood-brain barrier. J Med Chem. 2017;60:4510–6. [DOI] [PubMed]

75.

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;9:535. [DOI] [PubMed] [PMC]

76.

Guo S, Vieweger M, Zhang K, Yin H, Wang H, Li X, et al. Ultra-thermostable RNA nanoparticles for solubilizing and high-yield loading of paclitaxel for breast cancer therapy. Nat Commun. 2020;11:972. [DOI] [PubMed] [PMC]

77.

Belyanina IV, Zamay TN, Zamay GS, Zamay SS, Kolovskaya OS, Ivanchenko TI, et al. In vivo cancer cells elimination guided by aptamer-functionalized gold-coated magnetic nanoparticles and controlled with low frequency alternating magnetic field. Theranostics. 2017;7:3326–37. [DOI] [PubMed] [PMC]

78.

Feng X, Liu J, Xu W, Li G, Ding J. Tackling autoimmunity with nanomedicines. Nanomedicine (Lond). 2020;15:1585–97. [DOI] [PubMed]

79.

Feng X, Xu W, Li Z, Song W, Ding J, Chen X. Immunomodulatory nanosystems. Adv Sci (Weinh). 2019;6:1900101. [DOI] [PubMed] [PMC]

80.

Pastor F. Aptamers: A new technological platform in cancer immunotherapy. Pharmaceuticals (Basel). 2016;9:64. [DOI]

81.

Ravichandran G, Rengan AK. Aptamer-mediated nanotheranostics for cancer treatment: a review. ACS Appl Nano Mater. 2020;3:9542–59. [DOI]

82.

Bai C, Gao S, Hu S, Liu X, Li H, Dong J, et al. Self-assembled multivalent aptamer nanoparticles with potential CAR-like characteristics could activate T cells and inhibit melanoma growth. Mol Ther Oncolytics. 2020;17:9–20. [DOI] [PubMed] [PMC]

83.

Bouvier-Müller A, Ducongé F. Application of aptamers for in vivo molecular imaging and theranostics. Adv Drug Deliv Rev. 2018;134:94–106. [DOI] [PubMed]

84.

Camorani S, Hill BS, Collina F, Gargiulo S, Napolitano M, Cantile M, et al. Targeted imaging and inhibition of triple-negative breast cancer metastases by a PDGFRβ aptamer. Theranostics. 2018;8:5178–99. [DOI] [PubMed] [PMC]

85.

Kim MW, Jeong HY, Kang SJ, Jeong IH, Choi MJ, You YM, et al. Anti-EGF receptor aptamer-guided co-delivery of anti-cancer siRNAs and quantum dots for theranostics of triple-negative breast cancer. Theranostics. 2019;9:837–52. [DOI] [PubMed] [PMC]

86.

Tan J, Yang N, Zhong L, Tan J, Hu Z, Zhao Q, et al. A new theranostic system based on endoglin aptamer conjugated fluorescent silica nanoparticles. Theranostics. 2017;7:4862–76. [DOI] [PubMed] [PMC]

87.

Xiang D, Zheng C, Zhou SF, Qiao S, Tran PH, Pu C, et al. Superior performance of aptamer in tumor penetration over antibody: implication of aptamer-based theranostics in solid tumors. Theranostics. 2015;5:1083–97. [DOI] [PubMed] [PMC]

88.

Melancon MP, Zhou M, Zhang R, Xiong C, Allen P, Wen X, et al. Selective uptake and imaging of aptamer- and antibody-conjugated hollow nanospheres targeted to epidermal growth factor receptors overexpressed in head and neck cancer. ACS Nano. 2014;8:4530–8. [DOI] [PubMed] [PMC]

89.

Ajona D, Ortiz-Espinosa S, Moreno H, Lozano T, Pajares MJ, Agorreta J, et al. A combined PD-1/ C5a blockade synergistically protects against lung cancer growth and metastasis. Cancer Discov. 2017;7:694–703. [DOI] [PubMed]

90.

Gefen T, Castro I, Muharemagic D, Puplampu-Dove Y, Patel S, Gilboa E. A TIM-3 oligonucleotide aptamer enhances T cell functions and potentiates tumor immunity in mice. Mol Ther. 2017;25:2280–8. [DOI] [PubMed] [PMC]

91.

Cortés J, André F, Gonçalves A, Kümmel S, Martín M, Schmid P, et al. IMpassion132 phase III trial: atezolizumab and chemotherapy in early relapsing metastatic triple-negative breast cancer. Future Oncol. 2019;15:1951–61. [DOI] [PubMed]

92.

Camorani S, Passariello M, Agnello L, Esposito S, Collina F, Cantile M, et al. Aptamer targeted therapy potentiates immune checkpoint blockade in triple-negative breast cancer. J Exp Clin Cancer Res. 2020;39:180. [DOI] [PubMed] [PMC]

93.

Passariello M, Camorani S, Vetrei C, Cerchia L, De Lorenzo C. Novel human bispecific aptamer-antibody conjugates for efficient cancer cell killing. Cancers (Basel). 2019;11:1268. [DOI]

94.

Passariello M, Camorani S, Vetrei C, Ricci S, Cerchia L, De Lorenzo C. Ipilimumab and its derived EGFR aptamer-based conjugate induce efficient NK cell activation against cancer cells. Cancers (Basel). 2020;12:331. [DOI]

95.

Hori SI, Herrera A, Rossi JJ, Zhou J. Current advances in aptamers for cancer diagnosis and therapy. Cancers (Basel). 2018;10:9. [DOI]

96.

Hirose K, Tsuchida M, Asakura H, Wakui K, Yoshimoto K, Iida K, et al. A single-round selection of selective DNA aptamers for mammalian cells by polymer-enhanced capillary transient isotachophoresis. Analyst. 2017;142:4030–8. [DOI] [PubMed]

97.

Odeh F, Nsairat H, Alshaer W, Ismail MA, Esawi E, Qaqish B, et al. Aptamers chemistry: chemical modifications and conjugation strategies. Molecules. 2019;25:3. [DOI]

98.

Elskens JP, Elskens JM, Madder A. Chemical modification of aptamers for increased binding affinity in diagnostic applications: current status and future prospects. Int J Mol Sci. 2020;21:4522. [DOI]

99.

Dougherty CA, Cai W, Hong H. Applications of aptamers in targeted imaging: state of the art. Curr Top Med Chem. 2015;15:1138–52. [DOI] [PubMed] [PMC]

100.

Ni S, Zhuo Z, Pan Y, Yu Y, Li F, Liu J, et al. Recent progress in aptamer discoveries and modifications for therapeutic applications. ACS Appl Mater Interfaces. 2020;[Epub ahead of print].

101.

Global aptamer market research report 2019 [Internet]. Selbyville: Market Study Report; c2019 [cited 2020 Dec 09]. Available from: https://www.marketstudyreport.com/reports/global-aptamer-market-research-report-2019