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13 pages, 2052 KiB

Open AccessArticle

An Aptamer That Rapidly Internalizes into Cancer Cells Utilizes the Transferrin Receptor Pathway

by Xirui Song, Haixiang Yu, Cynthia Sullenger, Bethany Powell Gray, Amy Yan, Linsley Kelly and Bruce Sullenger

Cancers 2023, 15(8), 2301; https://doi.org/10.3390/cancers15082301 - 14 Apr 2023

Viewed by 2061

Abstract

Strategies to direct drugs specifically to cancer cells have been increasingly explored, and significant progress has been made toward such targeted therapy. For example, drugs have been conjugated into tumor-targeting antibodies to enable delivery directly to tumor cells. Aptamers are an attractive class [...] Read more.

Strategies to direct drugs specifically to cancer cells have been increasingly explored, and significant progress has been made toward such targeted therapy. For example, drugs have been conjugated into tumor-targeting antibodies to enable delivery directly to tumor cells. Aptamers are an attractive class of molecules for this type of drug targeting as they are high-affinity/high-specificity ligands, relatively small in size, GMP manufacturable at a large-scale, amenable to chemical conjugation, and not immunogenic. Previous work from our group revealed that an aptamer selected to internalize into human prostate cancer cells, called E3, can also target a broad range of human cancers but not normal control cells. Moreover, this E3 aptamer can deliver highly cytotoxic drugs to cancer cells as Aptamer-highly Toxic Drug Conjugates (ApTDCs) and inhibit tumor growth in vivo. Here, we evaluate its targeting mechanism and report that E3 selectively internalizes into cancer cells utilizing a pathway that involves transferrin receptor 1 (TfR 1). E3 binds to recombinant human TfR 1 with high affinity and competes with transferrin (Tf) for binding to TfR1. In addition, knockdown or knockin of human TfR1 results in a decrease or increase in E3 cell binding. Here, we reported a molecular model of E3 binding to the transferrin receptor that summarizes our findings. Full article

(This article belongs to the Special Issue Aptamers and Cancer)

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13 pages, 2237 KiB

Open AccessArticle

Targeted-Lymphoma Drug Delivery System Based on the Sgc8-c Aptamer

by Estefanía Sicco, Hugo Cerecetto, Victoria Calzada and María Moreno

Cancers 2023, 15(3), 922; https://doi.org/10.3390/cancers15030922 - 01 Feb 2023

Cited by 2 | Viewed by 1757

Abstract

Aptamers are emerging as a promising new class of functional nucleic acids because they can specifically bind to any target with high affinity and be easily modified chemically with different pharmacophoric subunits for therapy. The truncated aptamer, Sgc8-c, binds to tyrosine-protein kinase-like 7 [...] Read more.

Aptamers are emerging as a promising new class of functional nucleic acids because they can specifically bind to any target with high affinity and be easily modified chemically with different pharmacophoric subunits for therapy. The truncated aptamer, Sgc8-c, binds to tyrosine-protein kinase-like 7 receptor, a promising cancer therapeutic target, allowing the recognition of haemato-oncological malignancies, among others. We have previously developed aptamer-drug conjugates by chemical synthesis, hybridizing Sgc8-c and dasatinib, a drug proposed for lymphoma chemotherapy. One of the best-characterised Sgc8-c-dasatinib hybrids, namely Sgc8-c-carb-da, was capable of releasing dasatinib at an endosomal-pH. Herein, we probed the therapeutic potential of this aptamer-drug conjugate. Sgc8-c-carb-da specifically inhibited murine A20 B lymphocyte growth and produced cell death, mainly by late apoptosis and necrosis. In addition, Sgc8-c-carb-da generated an arrest in cell proliferation, with a cell cycle arrest in the Sub-G1-peak. The mitochondrial potential was altered accordingly to these pathways. Moreover, using an in vitro cell-targeting assay that mimics in vivo conditions, we showed that Sgc8-c-carb-da displayed higher (2.5-fold) cytotoxic effects than dasatinib. These findings provide proof-of-concept of the therapeutic value of Sgc8-c-carb-da for lymphoma, creating new opportunities for the chemical synthesis of targeted biotherapeutics. Full article

(This article belongs to the Special Issue Aptamers and Cancer)

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19 pages, 3275 KiB

Open AccessArticle

Identification and Characterization of Aptamers Targeting Ovarian Cancer Biomarker Human Epididymis Protein 4 for the Application in Urine

by Antonija Hanžek, Frédéric Ducongé, Christian Siatka and Anne-Cécile E. Duc

Cancers 2023, 15(2), 452; https://doi.org/10.3390/cancers15020452 - 10 Jan 2023

Cited by 3 | Viewed by 2145

Abstract

Ovarian cancer is the deadliest gynecological cancer. With non-specific symptoms of the disease and the lack of effective diagnostic methods, late diagnosis remains the crucial hurdle of the poor prognosis. Therefore, development of novel diagnostic approaches are needed. The purpose of this study [...] Read more.

Ovarian cancer is the deadliest gynecological cancer. With non-specific symptoms of the disease and the lack of effective diagnostic methods, late diagnosis remains the crucial hurdle of the poor prognosis. Therefore, development of novel diagnostic approaches are needed. The purpose of this study is to develop DNA-based aptamers as potential diagnostic probes to detect ovarian cancer biomarker Human epididymis protein 4 (HE4) in urine. HE4 is a protein overexpressed in ovarian cancer, but not in healthy or benign conditions. With high stability and diagnostic value for detection of ovarian cancer, urine HE4 appears as an attractive non-invasive biomarker. The high-affinity anti-HE4 DNA aptamers were selected through 10 cycles of High Fidelity Systematic Evolution of Ligands by EXponential enrichment (Hi-Fi SELEX), a method for aptamer selection based on digital droplet PCR. The anti-HE4 aptamers were identified using DNA sequencing and bioinformatics analysis. The candidate aptamer probes were characterized in urine for binding to HE4 protein using thermofluorimetry. Two anti-HE4 aptamers, AHE1 and AHE3, displayed binding to HE4 protein in urine, with a constant of dissociation in the nanomolar range, with K_d (AHE1) = 87 ± 9 nM and K_d (AHE3) aptamer of 127 ± 28 nM. Therefore, these aptamers could be promising tools for application in diagnostics and future development of urine tests or biosensors for ovarian cancer. Full article

(This article belongs to the Special Issue Aptamers and Cancer)

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21 pages, 2864 KiB

Open AccessArticle

Potential Therapeutic Use of Aptamers against HAT1 in Lung Cancer

by José Ignacio Klett-Mingo, Celia Pinto-Díez, Julio Cambronero-Plaza, Rebeca Carrión-Marchante, Miriam Barragán-Usero, María Isabel Pérez-Morgado, Eulalia Rodríguez-Martín, Mª Val Toledo-Lobo, Víctor M González and M. Elena Martín

Cancers 2023, 15(1), 227; https://doi.org/10.3390/cancers15010227 - 30 Dec 2022

Cited by 3 | Viewed by 1662

Abstract

Lung cancer is one of the leading causes of death worldwide and the most common of all cancer types. Histone acetyltransferase 1 (HAT1) has attracted increasing interest as a potential therapeutic target due to its involvement in multiple pathologies, including cancer. Aptamers are [...] Read more.

Lung cancer is one of the leading causes of death worldwide and the most common of all cancer types. Histone acetyltransferase 1 (HAT1) has attracted increasing interest as a potential therapeutic target due to its involvement in multiple pathologies, including cancer. Aptamers are single-stranded RNA or DNA molecules whose three-dimensional structure allows them to bind to a target molecule with high specificity and affinity, thus making them exceptional candidates for use as diagnostic or therapeutic tools. In this work, aptamers against HAT1 were obtained, subsequently characterized, and optimized, showing high affinity and specificity for HAT1 and the ability to inhibit acetyltransferase activity in vitro. Of those tested, the apHAT610 aptamer reduced cell viability, induced apoptosis and cell cycle arrest, and inhibited colony formation in lung cancer cell lines. All these results indicate that the apHAT610 aptamer is a potential drug for the treatment of lung cancer. Full article

(This article belongs to the Special Issue Aptamers and Cancer)

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17 pages, 3386 KiB

Open AccessArticle

Aptamer-Based Sandwich Assay Formats for Detection and Discrimination of Human High- and Low-Molecular-Weight uPA for Cancer Prognosis and Diagnosis

by Nico Dreymann, Wiebke Sabrowski, Jennifer Danso and Marcus M. Menger

Cancers 2022, 14(21), 5222; https://doi.org/10.3390/cancers14215222 - 25 Oct 2022

Cited by 2 | Viewed by 1996

Abstract

Urokinase-type plasminogen activator (urokinase, uPA) is a frequently discussed biomarker for prognosis, diagnosis, and recurrence of cancer. In a previous study, we developed ssDNA aptamers that bind to different forms of human urokinase, which are therefore assumed to have different binding regions. In [...] Read more.

Urokinase-type plasminogen activator (urokinase, uPA) is a frequently discussed biomarker for prognosis, diagnosis, and recurrence of cancer. In a previous study, we developed ssDNA aptamers that bind to different forms of human urokinase, which are therefore assumed to have different binding regions. In this study, we demonstrate the development of aptamer-based sandwich assays that use different combinations of these aptamers to detect high molecular weight- (HMW-) uPA in a micro titer plate format. By combining aptamers and antibodies, it was possible to distinguish between HMW-uPA and low molecular weight- (LMW-) uPA. For the best performing aptamer combination, we calculated the limit of detection (LOD) and limit of quantification (LOQ) in spiked buffer and urine samples with an LOD up to 50 ng/mL and 138 ng/mL, respectively. To show the specificity and sequence dependence of the reporter aptamer uPAapt−02−FR, we have identified key nucleotides within the sequence that are important for specific folding and binding to uPA using a fluorescent dye-linked aptamer assay (FLAA). Since uPA is a much-discussed marker for prognosis and diagnosis in various types of cancers, these aptamers and their use in a micro titer plate assay format represent a novel, promising tool for the detection of uPA and for possible diagnostic applications. Full article

(This article belongs to the Special Issue Aptamers and Cancer)

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Review

Jump to: Research

41 pages, 3221 KiB

Open AccessReview

Aptamers as Potential Therapeutic Tools for Ovarian Cancer: Advancements and Challenges

by Wojciech Szymanowski, Anna Szymanowska, Anna Bielawska, Gabriel Lopez-Berestein, Cristian Rodriguez-Aguayo and Paola Amero

Cancers 2023, 15(21), 5300; https://doi.org/10.3390/cancers15215300 - 06 Nov 2023

Cited by 1 | Viewed by 1500

Abstract

Ovarian cancer (OC) is the most common lethal gynecologic cause of death in women worldwide, with a high mortality rate and increasing incidence. Despite advancements in the treatment, most OC patients still die from their disease due to late-stage diagnosis, the lack of [...] Read more.

Ovarian cancer (OC) is the most common lethal gynecologic cause of death in women worldwide, with a high mortality rate and increasing incidence. Despite advancements in the treatment, most OC patients still die from their disease due to late-stage diagnosis, the lack of effective diagnostic methods, and relapses. Aptamers, synthetic, short single-stranded oligonucleotides, have emerged as promising anticancer therapeutics. Their ability to selectively bind to target molecules, including cancer-related proteins and receptors, has revolutionized drug discovery and biomarker identification. Aptamers offer unique insights into the molecular pathways involved in cancer development and progression. Moreover, they show immense potential as drug delivery systems, enabling targeted delivery of therapeutic agents to cancer cells while minimizing off-target effects and reducing systemic toxicity. In the context of OC, the integration of aptamers with non-coding RNAs (ncRNAs) presents an opportunity for precise and efficient gene targeting. Additionally, the conjugation of aptamers with nanoparticles allows for accurate and targeted delivery of ncRNAs to specific cells, tissues, or organs. In this review, we will summarize the potential use and challenges associated with the use of aptamers alone or aptamer–ncRNA conjugates, nanoparticles, and multivalent aptamer-based therapeutics for the treatment of OC. Full article

(This article belongs to the Special Issue Aptamers and Cancer)

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21 pages, 651 KiB

Open AccessReview

Modulating T Cell Responses by Targeting CD3

by Ashwathi Puravankara Menon, Beatriz Moreno, Daniel Meraviglia-Crivelli, Francesca Nonatelli, Helena Villanueva, Martin Barainka, Angelina Zheleva, Hisse M. van Santen and Fernando Pastor

Cancers 2023, 15(4), 1189; https://doi.org/10.3390/cancers15041189 - 13 Feb 2023

Cited by 8 | Viewed by 5897

Abstract

Harnessing the immune system to fight cancer has become a reality with the clinical success of immune-checkpoint blockade (ICB) antibodies against PD(L)-1 and CTLA-4. However, not all cancer patients respond to ICB. Thus, there is a need to modulate the immune system through [...] Read more.

Harnessing the immune system to fight cancer has become a reality with the clinical success of immune-checkpoint blockade (ICB) antibodies against PD(L)-1 and CTLA-4. However, not all cancer patients respond to ICB. Thus, there is a need to modulate the immune system through alternative strategies for improving clinical responses to ICB. The CD3-T cell receptor (TCR) is the canonical receptor complex on T cells. It provides the “first signal” that initiates T cell activation and determines the specificity of the immune response. The TCR confers the binding specificity whilst the CD3 subunits facilitate signal transduction necessary for T cell activation. While the mechanisms through which antigen sensing and signal transduction occur in the CD3–TCR complex are still under debate, recent revelations regarding the intricate 3D structure of the CD3–TCR complex might open the possibility of modulating its activity by designing targeted drugs and tools, including aptamers. In this review, we summarize the basis of CD3–TCR complex assembly and survey the clinical and preclinical therapeutic tools available to modulate CD3–TCR function for potentiating cancer immunotherapy. Full article

(This article belongs to the Special Issue Aptamers and Cancer)

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27 pages, 2053 KiB

Open AccessReview

The Research Advances of Aptamers in Hematologic Malignancies

by Yongkang Liao, Shijun Xiong, Zaid Ur Rehman, Xiaoli He, Hongling Peng, Jing Liu and Shuming Sun

Cancers 2023, 15(1), 300; https://doi.org/10.3390/cancers15010300 - 01 Jan 2023

Cited by 2 | Viewed by 2588

Abstract

Currently, research for hematological malignancies is very intensive, with many breakthroughs. Among them, aptamer-based targeted therapies could be counted. Aptamer is a targeting tool with many unique advantages (easy synthesis, low toxicity, easy modification, low immunogenicity, nano size, long stability, etc.), therefore many [...] Read more.

Currently, research for hematological malignancies is very intensive, with many breakthroughs. Among them, aptamer-based targeted therapies could be counted. Aptamer is a targeting tool with many unique advantages (easy synthesis, low toxicity, easy modification, low immunogenicity, nano size, long stability, etc.), therefore many experts screened corresponding aptamers in various hematological malignancies for diagnosis and treatment. In this review, we try to summarize and provide the recent progress of aptamer research in the diagnosis and treatment of hematologic malignancies. Until now, 29 aptamer studies were reported in hematologic malignancies, of which 12 aptamers were tested in vivo and the remaining 17 aptamers were only tested in vitro. In this case, 11 aptamers were combined with chemotherapeutic drugs for the treatment of hematologic malignancies, 4 aptamers were used in combination with nanomaterials for the diagnosis and treatment of hematologic malignancies, and some studies used aptamers for the targeted transportation of siRNA and miRNA for targeted therapeutic effects. Their research provides multiple approaches to achieve more targeted goals. These findings show promising and encouraging future for both hematological malignancies basic and clinical trials research. Full article

(This article belongs to the Special Issue Aptamers and Cancer)

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13 pages, 775 KiB

Open AccessReview

Aptamers, a New Therapeutic Opportunity for the Treatment of Multiple Myeloma

by Ane Amundarain, Fernando Pastor, Felipe Prósper and Xabier Agirre

Cancers 2022, 14(21), 5471; https://doi.org/10.3390/cancers14215471 - 07 Nov 2022

Cited by 1 | Viewed by 1868

Abstract

Multiple Myeloma (MM) remains an incurable disease due to high relapse rates and fast development of drug resistances. The introduction of monoclonal antibodies (mAb) has caused a paradigm shift in MM treatment, paving the way for targeted approaches with increased efficacy and reduced [...] Read more.

Multiple Myeloma (MM) remains an incurable disease due to high relapse rates and fast development of drug resistances. The introduction of monoclonal antibodies (mAb) has caused a paradigm shift in MM treatment, paving the way for targeted approaches with increased efficacy and reduced toxicities. Nevertheless, antibody-based therapies face several difficulties such as high immunogenicity, high production costs and limited conjugation capacity, which we believe could be overcome by the introduction of nucleic acid aptamers. Similar to antibodies, aptamers can bind to their targets with great affinity and specificity. However, their chemical nature reduces their immunogenicity and production costs, while it enables their conjugation to a wide variety of cargoes for their use as delivery agents. In this review, we summarize several aptamers that have been tested against MM specific targets with promising results, establishing the rationale for the further development of aptamer-based strategies against MM. In this direction, we believe that the study of novel plasma cell surface markers, the development of intracellular aptamers and further research on aptamers as building blocks for complex nanomedicines will lead to the generation of next-generation targeted approaches that will undoubtedly contribute to improve the management and life quality of MM patients. Full article

(This article belongs to the Special Issue Aptamers and Cancer)

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