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Cancers
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The Role of Aptamers in Cancer Diagnostics and Therapy
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The Role of Aptamers in Cancer Diagnostics and Therapy

A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: closed (31 July 2020) | Viewed by 42020

Special Issue Editor

Prof. Dr. Maxim V. Berezovski

E-Mail Website
Guest Editor
Department of Chemistry and Biomolecular Sciences, University of Ottawa, Ottawa, ON K1N 6N5, Canada
Interests: glioblastoma; lung cancer; molecular diagnostics; circulating tumor cells; tumor-derived exosomes; aptamers; proteomics; biomarkers
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The ability of nucleic acid and peptide aptamers to bind to cancer biomarkers with high affinity and specificity, as well as their ease of production, has made them great candidates for their use as capture agents, imaging probes, and anticancer drugs. Aptamers offer antibodies’ functionality, but that can be easily engineered without animals, chemically synthesized, and modified with different chemical groups.

Novel aptamer technologies are gaining momentum in cancer research. Aptamer-based diagnostics can detect soluble and cell surface cancer biomarkers in a wide dynamic range and increased sensitivity. Aptamer-facilitated biomarker discovery reveals new tumor proteins. Aptamer-assisted cell imaging brings new advantages for enhanced detection of primary tumors and metastases. Aptamer-based therapeutics block the interaction of cancer-associated targets or activate the function of target receptors. Aptamers could also deliver small interfering RNAs, microRNAs, antimiRs, small molecule drugs or toxins, magnetic nanoparticles and immune cells to diseased cells and cause a therapeutic effect.

This Special Issue is aimed at summarizing both analytical developments and clinical evidence regarding the application of aptamers across the major cancer types, with a special focus on advantages and limitations of aptamer nanotechnologies.

Prof. Dr. Maxim V. Berezovski
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • aptamers
  • SELEX
  • in vitro evolution
  • aptamer-based ELISA-like assay
  • aptamer-facilitated biomarker discovery
  • aptamer–drug conjugates
  • aptamer-conjugated nanoparticles
  • aptamer chimeras
  • bifunctional aptamers
  • targeted therapy
  • cell and tumor imaging
  • circulating tumors cells
  • extracellular vesicles

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Published Papers (10 papers)

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Research

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23 pages, 3295 KiB  
Article
Identification of Potential Serum Protein Biomarkers and Pathways for Pancreatic Cancer Cachexia Using an Aptamer-Based Discovery Platform
by Ashok Narasimhan, Safi Shahda, Joshua K. Kays, Susan M. Perkins, Lijun Cheng, Katheryn N. H. Schloss, Daniel E. I. Schloss, Leonidas G. Koniaris and Teresa A. Zimmers
Cancers 2020, 12(12), 3787; https://doi.org/10.3390/cancers12123787 - 15 Dec 2020
Cited by 29 | Viewed by 5148
Abstract
Patients with pancreatic ductal adenocarcinoma (PDAC) suffer debilitating and deadly weight loss, known as cachexia. Development of therapies requires biomarkers to diagnose, and monitor cachexia; however, no such markers are in use. Via Somascan, we measured ~1300 plasma proteins in 30 patients with [...] Read more.
Patients with pancreatic ductal adenocarcinoma (PDAC) suffer debilitating and deadly weight loss, known as cachexia. Development of therapies requires biomarkers to diagnose, and monitor cachexia; however, no such markers are in use. Via Somascan, we measured ~1300 plasma proteins in 30 patients with PDAC vs. 11 controls. We found 60 proteins specific to local PDAC, 46 to metastatic, and 67 to presence of >5% cancer weight loss (FC ≥ |1.5|, p ≤ 0.05). Six were common for cancer stage (Up: GDF15, TIMP1, IL1RL1; Down: CCL22, APP, CLEC1B). Four were common for local/cachexia (C1R, PRKCG, ELANE, SOST: all oppositely regulated) and four for metastatic/cachexia (SERPINA6, PDGFRA, PRSS2, PRSS1: all consistently changed), suggesting that stage and cachexia status might be molecularly separable. We found 71 proteins that correlated with cachexia severity via weight loss grade, weight loss, skeletal muscle index and radiodensity (r ≥ |0.50|, p ≤ 0.05), including some known cachexia mediators/markers (LEP, MSTN, ALB) as well as novel proteins (e.g., LYVE1, C7, F2). Pathway, correlation, and upstream regulator analyses identified known (e.g., IL6, proteosome, mitochondrial dysfunction) and novel (e.g., Wnt signaling, NK cells) mechanisms. Overall, this study affords a basis for validation and provides insights into the processes underpinning cancer cachexia. Full article
(This article belongs to the Special Issue The Role of Aptamers in Cancer Diagnostics and Therapy)
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18 pages, 3624 KiB  
Article
An Aptamer for Broad Cancer Targeting and Therapy
by Bethany Powell Gray, Xirui Song, David S. Hsu, Christina Kratschmer, Matthew Levy, Ashley P. Barry and Bruce A. Sullenger
Cancers 2020, 12(11), 3217; https://doi.org/10.3390/cancers12113217 - 31 Oct 2020
Cited by 15 | Viewed by 3843
Abstract
Recent advances in chemotherapy treatments are increasingly targeted therapies, with the drug conjugated to an antibody able to deliver it directly to the tumor. As high-affinity chemical ligands that are much smaller in size, aptamers are ideal for this type of drug targeting. [...] Read more.
Recent advances in chemotherapy treatments are increasingly targeted therapies, with the drug conjugated to an antibody able to deliver it directly to the tumor. As high-affinity chemical ligands that are much smaller in size, aptamers are ideal for this type of drug targeting. Aptamer-highly toxic drug conjugates (ApTDCs) based on the E3 aptamer, selected on prostate cancer cells, target and inhibit prostate tumor growth in vivo. Here, we observe that E3 also broadly targets numerous other cancer types, apparently representing a universal aptamer for cancer targeting. Accordingly, ApTDCs formed by conjugation of E3 to the drugs monomethyl auristatin E (MMAE) or monomethyl auristatin F (MMAF) efficiently target and kill a range of different cancer cells. Notably, this targeting extends to both patient-derived explant (PDX) cancer cell lines and tumors, with the E3 MMAE and MMAF conjugates inhibiting PDX cell growth in vitro and with the E3 aptamer targeting PDX colorectal tumors in vivo. Full article
(This article belongs to the Special Issue The Role of Aptamers in Cancer Diagnostics and Therapy)
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16 pages, 1499 KiB  
Article
Combined Targeting of Glioblastoma Stem-Like Cells by Neutralizing RNA-Bio-Drugs for STAT3
by Carla Lucia Esposito, Silvia Nuzzo, Maria Luigia Ibba, Lucia Ricci-Vitiani, Roberto Pallini, Gerolama Condorelli, Silvia Catuogno and Vittorio de Franciscis
Cancers 2020, 12(6), 1434; https://doi.org/10.3390/cancers12061434 - 31 May 2020
Cited by 14 | Viewed by 3344
Abstract
An important drawback in the management of glioblastoma (GBM) patients is the frequent relapse upon surgery and therapy. A likely explanation is that conventional therapies poorly affect a small population of stem-like cancer cells (glioblastoma stem cells, GSCs) that remain capable of repopulating [...] Read more.
An important drawback in the management of glioblastoma (GBM) patients is the frequent relapse upon surgery and therapy. A likely explanation is that conventional therapies poorly affect a small population of stem-like cancer cells (glioblastoma stem cells, GSCs) that remain capable of repopulating the tumour mass. Indeed, the development of therapeutic strategies able to hit GSCs while reducing the tumour burden has become an important challenge to increase a patient’s survival. The signal transducer and activator of transcription-3 (STAT3) has been reported to play a pivotal role in maintaining the tumour initiating capacity of the GSC population. Therefore, in order to impair the renewal and propagation of the PDGFRβ-expressing GSC population, here we took advantage of the aptamer–siRNA chimera (AsiC), named Gint4.T-STAT3, that we previously have shown to efficiently antagonize STAT3 in subcutaneous PDGFRβ-positive GBM xenografts. We demonstrate that the aptamer conjugate is able to effectively and specifically prevent patient-derived GSC function and expansion. Moreover, because of the therapeutic potential of using miR-10b inhibitors and of the broad expression of the Axl receptor in GBM, we used the GL21.T anti-Axl aptamer as the targeting moiety for anti-miR-10b, showing that, in combination with the STAT3 AsiC, the aptamer–miR-10b antagonist treatment further enhances the inhibition of GSC sphere formation. Our results highlight the potential to use a combined approach with targeted RNA therapeutics to inhibit GBM tumour dissemination and relapse. Full article
(This article belongs to the Special Issue The Role of Aptamers in Cancer Diagnostics and Therapy)
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12 pages, 4464 KiB  
Article
Suicide Gene Therapy Mediated with Exosomes Produced by Mesenchymal Stem/Stromal Cells Stably Transduced with HSV Thymidine Kinase
by Andrea Pastorakova, Jana Jakubechova, Ursula Altanerova and Cestmir Altaner
Cancers 2020, 12(5), 1096; https://doi.org/10.3390/cancers12051096 - 28 Apr 2020
Cited by 19 | Viewed by 3899
Abstract
Mesenchymal stem/stromal cells (MSCs) prepared from various human tissues were stably transduced with the suicide gene herpes simplex virus thymidine kinase (HSVTK) by means of retrovirus infection. HSVTK-transduced MSCs express the suicide gene and in prodrug ganciclovir (GCV) presence induced cell [...] Read more.
Mesenchymal stem/stromal cells (MSCs) prepared from various human tissues were stably transduced with the suicide gene herpes simplex virus thymidine kinase (HSVTK) by means of retrovirus infection. HSVTK-transduced MSCs express the suicide gene and in prodrug ganciclovir (GCV) presence induced cell death by intracellular conversion of GCV to GCV-triphosphate. The homogenous population of HSVTK-MSCs were found to release exosomes having mRNA of the suicide gene in their cargo. The exosomes were easily internalized by the tumor cells and the presence of ganciclovir caused their death in a dose-dependent manner. Efficient tumor cell killing of glioma cell lines and primary human glioblastoma cells mediated by HSVTK-MSC exosomes is reported. Exosomes produced by suicide gene transduced MSCs represent a new class of highly selective tumor cell targeted drug acting intracellular with curative potential. Full article
(This article belongs to the Special Issue The Role of Aptamers in Cancer Diagnostics and Therapy)
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13 pages, 3671 KiB  
Article
Aptamer-Equipped Protamine Nanomedicine for Precision Lymphoma Therapy
by Zihua Zeng, Ching-Hsuan Tung and Youli Zu
Cancers 2020, 12(4), 780; https://doi.org/10.3390/cancers12040780 - 25 Mar 2020
Cited by 18 | Viewed by 3442
Abstract
Anaplastic large cell lymphoma (ALCL) is the most common T-cell lymphoma in children. ALCL cells characteristically express surface CD30 molecules and carry the pathogenic ALK oncogene, both of which are diagnostic biomarkers and are also potential therapeutic targets. For precision therapy, we report [...] Read more.
Anaplastic large cell lymphoma (ALCL) is the most common T-cell lymphoma in children. ALCL cells characteristically express surface CD30 molecules and carry the pathogenic ALK oncogene, both of which are diagnostic biomarkers and are also potential therapeutic targets. For precision therapy, we report herein a protamine nanomedicine incorporated with oligonucleotide aptamers to selectively target lymphoma cells, a dsDNA/drug payload to efficiently kill targeted cells, and an siRNA to specifically silence ALK oncogenes. The aptamer-equipped protamine nanomedicine was simply fabricated through a non-covalent charge-force reaction. The products had uniform structure morphology under an electron microscope and a peak diameter of 103 nm by dynamic light scattering measurement. Additionally, flow cytometry analysis demonstrated that under CD30 aptamer guidance, the protamine nanomedicine specifically bound to lymphoma cells, but did not react to off-target cells in control experiments. Moreover, specific cell targeting and intracellular delivery of the nanomedicine were also validated by electron and confocal microscopy. Finally, functional studies demonstrated that, through combined cell-selective chemotherapy using a drug payload and oncogene-specific gene therapy using an siRNA, the protamine nanomedicine effectively killed lymphoma cells with little toxicity to off-target cells, indicating its potential for precision therapy. Full article
(This article belongs to the Special Issue The Role of Aptamers in Cancer Diagnostics and Therapy)
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18 pages, 3523 KiB  
Article
Ipilimumab and Its Derived EGFR Aptamer-Based Conjugate Induce Efficient NK Cell Activation against Cancer Cells
by Margherita Passariello, Simona Camorani, Cinzia Vetrei, Stefania Ricci, Laura Cerchia and Claudia De Lorenzo
Cancers 2020, 12(2), 331; https://doi.org/10.3390/cancers12020331 - 1 Feb 2020
Cited by 24 | Viewed by 4582
Abstract
The immune checkpoint CTLA-4 (cytotoxic T-lymphocyte-antigen 4), which inhibits the co-stimulatory CD28 signal on T cells, has been recently found expressed on other cell populations, such as tumor and natural killer (NK) cells. We tested for the first time the effects of ipilimumab, [...] Read more.
The immune checkpoint CTLA-4 (cytotoxic T-lymphocyte-antigen 4), which inhibits the co-stimulatory CD28 signal on T cells, has been recently found expressed on other cell populations, such as tumor and natural killer (NK) cells. We tested for the first time the effects of ipilimumab, the human anti-CTLA4 mAb in clinical use, on these cells and found that it inhibits the growth of tumor cells expressing CTLA-4 also in the absence of lymphocytes, and efficiently activates NK cells, thus suggesting an important unexplored role of NK cells in ipilimumab-modulated immune responses. Interestingly, the epidermal growth factor receptor (EGFR) has been shown to play a key role in tumor cell escape from immune surveillance, and in cytotoxic T lymphocyte inhibition. Thus, we tested combinatorial treatments of ipilimumab with an anti-EGFR aptamer endowed with anti-tumor activity, and constructed for the first time a novel bispecific immunoconjugate, made up of these two compounds. The novel immunoconjugate binds to the target cells, induces the activation of lymphocytes, including NK cells, and inhibits the growth of tumor target cells more efficiently than the parental compounds, by strongly enhancing the cytotoxic activity of both human peripheral blood mononuclear cells and NK cells against tumor cells. Full article
(This article belongs to the Special Issue The Role of Aptamers in Cancer Diagnostics and Therapy)
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17 pages, 5936 KiB  
Article
Aptamer-Conjugated Superparamagnetic Ferroarabinogalactan Nanoparticles for Targeted Magnetodynamic Therapy of Cancer
by Olga S. Kolovskaya, Tatiana N. Zamay, Galina S. Zamay, Vasily A. Babkin, Elena N. Medvedeva, Nadezhda A. Neverova, Andrey K. Kirichenko, Sergey S. Zamay, Ivan N. Lapin, Evgeny V. Morozov, Alexey E. Sokolov, Andrey A. Narodov, Dmitri G. Fedorov, Felix N. Tomilin, Vladimir N. Zabluda, Yulia Alekhina, Kirill A. Lukyanenko, Yury E. Glazyrin, Valery A. Svetlichnyi, Maxim V. Berezovski and Anna S. Kichkailoadd Show full author list remove Hide full author list
Cancers 2020, 12(1), 216; https://doi.org/10.3390/cancers12010216 - 15 Jan 2020
Cited by 32 | Viewed by 4957
Abstract
Nanotechnologies involving physical methods of tumor destruction using functional oligonucleotides are promising for targeted cancer therapy. Our study presents magnetodynamic therapy for selective elimination of tumor cells in vivo using DNA aptamer-functionalized magnetic nanoparticles exposed to a low frequency alternating magnetic field. We [...] Read more.
Nanotechnologies involving physical methods of tumor destruction using functional oligonucleotides are promising for targeted cancer therapy. Our study presents magnetodynamic therapy for selective elimination of tumor cells in vivo using DNA aptamer-functionalized magnetic nanoparticles exposed to a low frequency alternating magnetic field. We developed an enhanced targeting approach of cancer cells with aptamers and arabinogalactan. Aptamers to fibronectin (AS-14) and heat shock cognate 71 kDa protein (AS-42) facilitated the delivery of the nanoparticles to Ehrlich carcinoma cells, and arabinogalactan (AG) promoted internalization through asialoglycoprotein receptors. Specific delivery of the aptamer-modified FeAG nanoparticles to the tumor site was confirmed by magnetic resonance imaging (MRI). After the following treatment with a low frequency alternating magnetic field, AS-FeAG caused cancer cell death in vitro and tumor reduction in vivo. Histological analyses showed mechanical disruption of tumor tissues, total necrosis, cell lysis, and disruption of the extracellular matrix. The enhanced targeted magnetic theranostics with the aptamer conjugated superparamagnetic ferroarabinogalactans opens up a new venue for making biocompatible contrasting agents for MRI imaging and performing non-invasive anti-cancer therapies with a deep penetrated magnetic field. Full article
(This article belongs to the Special Issue The Role of Aptamers in Cancer Diagnostics and Therapy)
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Review

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29 pages, 1911 KiB  
Review
Aptamers: Novel Therapeutics and Potential Role in Neuro-Oncology
by Paola Amero, Soumen Khatua, Cristian Rodriguez-Aguayo and Gabriel Lopez-Berestein
Cancers 2020, 12(10), 2889; https://doi.org/10.3390/cancers12102889 - 9 Oct 2020
Cited by 20 | Viewed by 3822
Abstract
A relatively new paradigm in cancer therapeutics is the use of cancer cell–specific aptamers, both as therapeutic agents and for targeted delivery of anticancer drugs. After the first therapeutic aptamer was described nearly 25 years ago, and the subsequent first aptamer drug approved, [...] Read more.
A relatively new paradigm in cancer therapeutics is the use of cancer cell–specific aptamers, both as therapeutic agents and for targeted delivery of anticancer drugs. After the first therapeutic aptamer was described nearly 25 years ago, and the subsequent first aptamer drug approved, many efforts have been made to translate preclinical research into clinical oncology settings. Studies of aptamer-based technology have unveiled the vast potential of aptamers in therapeutic and diagnostic applications. Among pediatric solid cancers, brain tumors are the leading cause of death. Although a few aptamer-related translational studies have been performed in adult glioblastoma, the use of aptamers in pediatric neuro-oncology remains unexplored. This review will discuss the biology of aptamers, including mechanisms of targeting cell surface proteins, various modifications of aptamer structure to enhance therapeutic efficacy, the current state and challenges of aptamer use in neuro-oncology, and the potential therapeutic role of aptamers in pediatric brain tumors. Full article
(This article belongs to the Special Issue The Role of Aptamers in Cancer Diagnostics and Therapy)
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17 pages, 463 KiB  
Review
The Role of RNA and DNA Aptamers in Glioblastoma Diagnosis and Therapy: A Systematic Review of the Literature
by Silvia Nuzzo, Valentina Brancato, Alessandra Affinito, Marco Salvatore, Carlo Cavaliere and Gerolama Condorelli
Cancers 2020, 12(8), 2173; https://doi.org/10.3390/cancers12082173 - 5 Aug 2020
Cited by 24 | Viewed by 4515
Abstract
Glioblastoma (GBM) is the most lethal primary brain tumor of the central nervous system in adults. Despite advances in surgical and medical neuro-oncology, the median survival is about 15 months. For this reason, initial diagnosis, prognosis, and targeted therapy of GBM represent very [...] Read more.
Glioblastoma (GBM) is the most lethal primary brain tumor of the central nervous system in adults. Despite advances in surgical and medical neuro-oncology, the median survival is about 15 months. For this reason, initial diagnosis, prognosis, and targeted therapy of GBM represent very attractive areas of study. Aptamers are short three-dimensional structures of single-stranded nucleic acids (RNA or DNA), identified by an in vitro process, named systematic evolution of ligands by exponential enrichment (SELEX), starting from a partially random oligonucleotide library. They bind to a molecular target with high affinity and specificity and can be easily modified to optimize binding affinity and selectivity. Thanks to their properties (low immunogenicity and toxicity, long stability, and low production variability), a large number of aptamers have been selected against GBM biomarkers and provide specific imaging agents and therapeutics to improve the diagnosis and treatment of GBM. However, the use of aptamers in GBM diagnosis and treatment still represents an underdeveloped topic, mainly due to limited literature in the research world. On these bases, we performed a systematic review aimed at summarizing current knowledge on the new promising DNA and RNA aptamer-based molecules for GBM diagnosis and treatment. Thirty-eight studies from 2000 were included and investigated. Seventeen involved the use of aptamers for GBM diagnosis and 21 for GBM therapy. Our findings showed that a number of DNA and RNA aptamers are promising diagnostic and therapeutic tools for GBM management. Full article
(This article belongs to the Special Issue The Role of Aptamers in Cancer Diagnostics and Therapy)
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Other

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10 pages, 1284 KiB  
Commentary
Quantification of Receptor Occupancy by Ligand—An Understudied Class of Potential Biomarkers
by Suresh Veeramani and George J. Weiner
Cancers 2020, 12(10), 2956; https://doi.org/10.3390/cancers12102956 - 13 Oct 2020
Viewed by 3237
Abstract
Molecular complexes, such as ligand–receptor complexes, are vital for both health and disease and can be shed into the circulation in soluble form. Relatively little is known about the biology of soluble ligand–receptor complexes. The functional importance of such complexes and their potential [...] Read more.
Molecular complexes, such as ligand–receptor complexes, are vital for both health and disease and can be shed into the circulation in soluble form. Relatively little is known about the biology of soluble ligand–receptor complexes. The functional importance of such complexes and their potential use as clinical biomarkers in diagnosis and therapy remains underappreciated. Most traditional technologies used to study ligand–receptor complexes measure the individual levels of soluble ligands or receptors rather than the complexes themselves. The fraction of receptors occupied by ligand, and the potential clinical relevance of such information, has been largely overlooked. Here, we review the biological significance of soluble ligand–receptor complexes with a specific focus on their potential as biomarkers of cancer and other inflammatory diseases. In addition, we discuss a novel RNA aptamer-based technology, designated ligand–receptor complex-binding aptamers (LIRECAP), that can provide precise measurement of the fraction of a soluble receptor occupied by its ligand. The potential applicability of the LIRECAP technology as a biomarker discovery platform is also described. Full article
(This article belongs to the Special Issue The Role of Aptamers in Cancer Diagnostics and Therapy)
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