Abstract
New strategies for cell type-specific delivery need to be developed if RNA interference is to realize its full therapeutic potential. One possible approach is the use of aptamers to deliver siRNAs selectively to tumor cells with appropriate antigens displayed on the surface. We used an aptamer that binds specifically to PSMA, a cell surface glycoprotein found in abundance on prostate cancer cells, and joined its 3 end to a siRNA specific for Eukaryotic Elongation Factor 2 mRNA (EEF2). This is an attractive target for cancer therapy because inhibiting EEF2 causes the rapid arrest of protein synthesis, inducing apoptosis and leading ultimately to cell death. In order to enhance the therapeutic efficacy of the aptamer-siRNA, we increased the valency of the construct by rational design. Two anti-PSMA aptamers were designed such that each binding sequence could fold independently into its active conformation. Here we show specific cytotoxicity resulting from siRNA-induced silencing of EEF2, as well as specific delivery to PSMA-expressing prostate cancer cells. Increasing the valency of the aptamer resulted in enhanced cytotoxicity compared with the monovalent constructs. The results presented here demonstrate the usefulness of multivalent aptamer-based delivery vehicles for siRNA therapeutics.
Keywords: Cell-Specific Induction, Apoptosis, Aptamer-siRNA, glycoprotein, prostate cancer cells, anti-PSMA, cytotoxicity, monovalent constructs, Eukaryotic, Elongation Factor 2
Current Cancer Drug Targets
Title: Cell-Specific Induction of Apoptosis by Rationally Designed Bivalent Aptamer-siRNA Transcripts Silencing Eukaryotic Elongation Factor 2
Volume: 8 Issue: 7
Author(s): Ulrich Wullner, Inga Neef, Andreas Eller, Michael Kleines, Mehmet Kemal Tur and Stefan Barth
Affiliation:
Keywords: Cell-Specific Induction, Apoptosis, Aptamer-siRNA, glycoprotein, prostate cancer cells, anti-PSMA, cytotoxicity, monovalent constructs, Eukaryotic, Elongation Factor 2
Abstract: New strategies for cell type-specific delivery need to be developed if RNA interference is to realize its full therapeutic potential. One possible approach is the use of aptamers to deliver siRNAs selectively to tumor cells with appropriate antigens displayed on the surface. We used an aptamer that binds specifically to PSMA, a cell surface glycoprotein found in abundance on prostate cancer cells, and joined its 3 end to a siRNA specific for Eukaryotic Elongation Factor 2 mRNA (EEF2). This is an attractive target for cancer therapy because inhibiting EEF2 causes the rapid arrest of protein synthesis, inducing apoptosis and leading ultimately to cell death. In order to enhance the therapeutic efficacy of the aptamer-siRNA, we increased the valency of the construct by rational design. Two anti-PSMA aptamers were designed such that each binding sequence could fold independently into its active conformation. Here we show specific cytotoxicity resulting from siRNA-induced silencing of EEF2, as well as specific delivery to PSMA-expressing prostate cancer cells. Increasing the valency of the aptamer resulted in enhanced cytotoxicity compared with the monovalent constructs. The results presented here demonstrate the usefulness of multivalent aptamer-based delivery vehicles for siRNA therapeutics.
Export Options
About this article
Cite this article as:
Wullner Ulrich, Neef Inga, Eller Andreas, Kleines Michael, Tur Kemal Mehmet and Barth Stefan, Cell-Specific Induction of Apoptosis by Rationally Designed Bivalent Aptamer-siRNA Transcripts Silencing Eukaryotic Elongation Factor 2, Current Cancer Drug Targets 2008; 8 (7) . https://dx.doi.org/10.2174/156800908786241078
DOI https://dx.doi.org/10.2174/156800908786241078 |
Print ISSN 1568-0096 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-5576 |
Call for Papers in Thematic Issues
Advances in Cancer Biomarkers and Potential Drug Targets: From Diagnosis to Therapy
Cancer biomarkers play a crucial role in the diagnosis, prognosis, and treatment of cancer. They provide valuable information for cancer detection, risk assessment, treatment selection, and monitoring response to therapy. With advancements in molecular biology and high-throughput technologies, there has been an increasing interest in identifying and characterizing cancer biomarkers ...read more
Novel Therapeutic Approaches to Target Drug Resistant Tumors
With the development of disciplines such as chemical biology and molecular biology, the genes or proteins closely related to tumor occurrence and development have gradually become clear. Targeted therapies targeting these genes or proteins provide more effective methods for tumor treatment. Tumor targeted drugs generally only act on specific targets ...read more
ROLE OF IMMUNE AND GENOTOXIC RESPONSE BIOMARKERS IN TUMOR MICROENVIRONMENT IN CANCER DIAGNOSIS AND TREATMENT
Biological biomarkers have been used in medical research as an indicator of a normal or abnormal process inside the body, or of a disease. Nowadays, various researchers are in process to explore and investigate the biological markers for the early assessment of cancer. DNA Damage response (DDR) pathways and immune ...read more
Targeting the battlefield between host and tumor: basic research and clinical practice on reshaping tumor immune microenvironment
Immune system protects host against malignant tumors through effector cells and molecules. Cancer development and its response to therapy are regulated by inflammation, which either promotes or suppresses cancer progression. Chronic inflammation facilitates cancer progression and treatment resistance, whereas induction of acute inflammatory reactions often lead to anti-cancer immune responses. ...read more
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
Related Articles
-
Antifungal Therapy of Aspergillosis of the Central Nervous System and Aspergillus Endophthalmitis
Current Pharmaceutical Design Management of Inflammatory Bowel Disease Patients with a Cancer History
Current Drug Targets Regulating TRAIL Receptor-Induced Cell Death at the Membrane: A Deadly Discussion
Recent Patents on Anti-Cancer Drug Discovery Targeted Ultrasound Imaging of Cancer: An Emerging Technology on its Way to Clinics
Current Pharmaceutical Design Epidermal Growth Factor Receptor-Targeted Therapy of Colorectal Cancer with Panitumumab
Current Cancer Therapy Reviews Natural Products as Promising Antitumoral Agents in Breast Cancer: Mechanisms of Action and Molecular Targets.
Mini-Reviews in Medicinal Chemistry Expression and Prognostic Significance of the MMP Family Molecules in Bladder Cancer
Combinatorial Chemistry & High Throughput Screening Glycoconjugates in Cancer Therapy
Anti-Cancer Agents in Medicinal Chemistry Review of Current Chemoinformatic Tools for Modeling Important Aspects of CYPsmediated Drug Metabolism. Integrating Metabolism Data with Other Biological Profiles to Enhance Drug Discovery
Current Drug Metabolism Prostate Cancer Gene Expression Marker 1 (PCGEM1): A Patented Prostate- Specific Non-Coding Gene and Regulator of Prostate Cancer Progression
Recent Patents on DNA & Gene Sequences The Cancer Preventive Effects of Edible Mushrooms
Anti-Cancer Agents in Medicinal Chemistry Chemosensitization of Prostate Carcinoma Cells with a Receptor-directed Smac Conjugate
Medicinal Chemistry The Application of lncRNAs in Cancer Treatment and Diagnosis
Recent Patents on Anti-Cancer Drug Discovery Tumor Stem Cell Niches: A New Functional Framework for the Action of Anticancer Drugs
Recent Patents on Anti-Cancer Drug Discovery Signaling Through Rho GTPase Pathway as Viable Drug Target
Current Medicinal Chemistry IGF-I Abuse in Sport
Current Drug Abuse Reviews Soft Bipolar Spectrum and Staging in Bipolar Disorder
Current Psychiatry Reviews Circulating Tumor Cells: A Reliable Biomarker for Prostate Cancer Treatment Assessment?
Current Drug Metabolism Supertargeted Chemistry: Identifying Relationships Between Molecular Structures and their Sub-Cellular Distribution
Current Topics in Medicinal Chemistry Different Concepts of Drug Delivery in Disease Entities
Mini-Reviews in Medicinal Chemistry