Abstract
One approach to further improve the therapeutic efficacy of nanoparticles is employment of active targeting strategies. Bispecific antibodies (bsAbs) that bind to both tumor specific antigens on the cell surface and to haptens such as digoxigenin (Dig) can direct digoxigeninylated payloads to tumor cells. In this study, we investigate the potential of dendritic polyglycerol (dPG) conjugates, which consist of a doxorubicin (DOX) prodrug, Dig moiety, and a poly (ethylene glycol) (PEG) shell, in combination with bsAb, as a novel approach for targeted prodrug delivery. We could show successful binding of the bsAbs to dPGDigMal-DOX-PEG conjugates, as well as binding of these complexes to the cell surface of Lewis Y (LeY) expressing MCF-7 cells. Using flow cytometry, we could show the preferential binding of the targeting complex over the complex of control conjugate lacking Dig moieties. At concentrations that are usually applied for drug delivery, antibodycomplexed nanoparticles (independent of antibody specificity) released cytotoxic compounds into cells to the same degree as unmodified nanoparticles. This indicates that antibody-attachment does not interfere with the inherent cell binding and drug delivery properties of nanoparticles. At low doxorubicin concentrations and short incubation times, however, we were able to see a slightly increased target specific cytotoxicity in vitro which is mediated by complexation of the digoxigeninylated NP with the Dig-binding moiety of a bsAb that in turns direct the complexed bsAb to target cells. This study demonstrates the potential of digoxigeninylated dPG prodrug conjugates in combination with bsAbs as a new platform for targeted prodrug delivery into cancerous tissues. However the nanoparticle design needs to be further optimized for significant targeted delivery.
Keywords: Active targeting, bispecific antibodies, dendritic polyglycerol, doxorubicin, polymer therapeutic, targeted drug delivery.
Current Cancer Drug Targets
Title:Bispecific Antibodies for Targeted Delivery of Dendritic Polyglycerol (dPG) Prodrug Conjugates
Volume: 16 Issue: 7
Author(s): Fatemeh Sheikhi Mehrabadi, Juliane Adelmann, Shilpi Gupta, Stefanie Wedepohl, Marcelo Calderón, Ulrich Brinkmann and Rainer Haag
Affiliation:
Keywords: Active targeting, bispecific antibodies, dendritic polyglycerol, doxorubicin, polymer therapeutic, targeted drug delivery.
Abstract: One approach to further improve the therapeutic efficacy of nanoparticles is employment of active targeting strategies. Bispecific antibodies (bsAbs) that bind to both tumor specific antigens on the cell surface and to haptens such as digoxigenin (Dig) can direct digoxigeninylated payloads to tumor cells. In this study, we investigate the potential of dendritic polyglycerol (dPG) conjugates, which consist of a doxorubicin (DOX) prodrug, Dig moiety, and a poly (ethylene glycol) (PEG) shell, in combination with bsAb, as a novel approach for targeted prodrug delivery. We could show successful binding of the bsAbs to dPGDigMal-DOX-PEG conjugates, as well as binding of these complexes to the cell surface of Lewis Y (LeY) expressing MCF-7 cells. Using flow cytometry, we could show the preferential binding of the targeting complex over the complex of control conjugate lacking Dig moieties. At concentrations that are usually applied for drug delivery, antibodycomplexed nanoparticles (independent of antibody specificity) released cytotoxic compounds into cells to the same degree as unmodified nanoparticles. This indicates that antibody-attachment does not interfere with the inherent cell binding and drug delivery properties of nanoparticles. At low doxorubicin concentrations and short incubation times, however, we were able to see a slightly increased target specific cytotoxicity in vitro which is mediated by complexation of the digoxigeninylated NP with the Dig-binding moiety of a bsAb that in turns direct the complexed bsAb to target cells. This study demonstrates the potential of digoxigeninylated dPG prodrug conjugates in combination with bsAbs as a new platform for targeted prodrug delivery into cancerous tissues. However the nanoparticle design needs to be further optimized for significant targeted delivery.
Export Options
About this article
Cite this article as:
Mehrabadi Sheikhi Fatemeh, Adelmann Juliane , Gupta Shilpi , Wedepohl Stefanie , Calderón Marcelo , Brinkmann Ulrich and Haag Rainer , Bispecific Antibodies for Targeted Delivery of Dendritic Polyglycerol (dPG) Prodrug Conjugates, Current Cancer Drug Targets 2016; 16 (7) . https://dx.doi.org/10.2174/1568009616666160208142910
DOI https://dx.doi.org/10.2174/1568009616666160208142910 |
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
Innovative Cancer Drug Targets: A New Horizon in Oncology
Cancer remains one of the most challenging diseases, with its complexity and adaptability necessitating continuous research efforts into more effective and targeted therapeutic approaches. Recent years have witnessed significant progress in understanding the molecular and genetic basis of cancer, leading to the identification of novel drug targets. These include, but ...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
![](/images/wayfinder.jpg)
- 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
-
Lung Cancer Chemotherapy, New Treatment and Related Patents
Recent Patents on Anti-Cancer Drug Discovery The Role of Mammalian Target of Rapamycin (mTOR) Inhibitors in the Treatment of Solid Tumors
Current Cancer Therapy Reviews Targeted Therapies in the Treatment of Advanced Renal Cell Carcinoma
Recent Patents on Anti-Cancer Drug Discovery Immunomodulation Mechanism of Antidepressants: Interactions between Serotonin/Norepinephrine Balance and Th1/Th2 Balance
Current Neuropharmacology Raloxifene and Cardiovascular Health: Its Relationship to Lipid and Glucose Metabolism, Hemostatic and Inflammation Factors and Cardiovascular Function in Postmenopausal Women
Current Pharmaceutical Design Physiology, Pharmacology and Pathophysiology of the pH Regulatory Transport Proteins NHE1 and NBCn1: Similarities, Differences, and Implications for Cancer Therapy
Current Pharmaceutical Design Angiomodulatory and Neurological Effects of Ginsenosides
Current Medicinal Chemistry The IGF Axis in Prostate Cancer
Current Pharmaceutical Design Inhibitors of 17β-Hydroxysteroid Dehydrogenases
Current Medicinal Chemistry Bioactive Compounds from Polar Regions: An Account of Chemical Ecology and Biotechnological Applications
Current Organic Chemistry Third and Fourth Generation Fluoroquinolone Antibacterials: A Systematic Review of Safety and Toxicity Profiles
Current Drug Safety HERVs Role in the Pathogenesis, Diagnosis or Prognosis of Aging Diseases: A Systematic Review
Current Molecular Medicine Cyclophilin function in Cancer; lessons from virus replication
Current Molecular Pharmacology Linear Poly(ethylenimine) Cross-Linked by Methyl-β-Cyclodextrin for Gene Delivery
Current Gene Therapy Unique Medicinal Properties of Withania somnifera: Phytochemical Constituents and Protein Component
Current Pharmaceutical Design Editorial (Thematic Issue: Mitochondria in Human Diseases and Animal Evolution)
Current Molecular Medicine Strategies that Target Tight Junctions for Enhanced Drug Delivery
Current Pharmaceutical Design A Short Course on Virology / Vectorology / Gene Therapy
Current Gene Therapy Natural Products and Cancer Stem Cells
Current Pharmaceutical Design Nucleic Acids as Therapeutic Agents
Current Topics in Medicinal Chemistry