Abstract
Tumor-specific delivery of ligand-directed prodrugs can increase the therapeutic window of chemotherapeutics by maintaining efficacy whilst decreasing toxic side effects. We have previously described a series of synthetic Nalkylated isatin cytotoxins that destabilize microtubules and induce apoptosis with 10-fold greater potency than conventional anti-mitotics in vitro. Here, we report the characterization, in vitro cytotoxicity and in vivo efficacy of a lead compound, 5,7-dibromo-N-(p-hydroxymethylbenzyl)isatin (N-AI) conjugated via an esterase-labile linker (N-AIE) to two proven targeting ligands, transferrin (Tf) and plasminogen activator inhibitor type 2 (PAI-2/serpinB2). N-AI was released from N-AIE and the targeting ligands Tf/PAI-2 in an esterase-dependent manner at 37 °C and both Tf- and PAI-2-N-AIE conjugates were stable at physiological pH. Human cancer cell lines which vary in their expression levels of Tf receptor (TfR/CD71) and PAI-2 target, receptor bound urokinase (uPA) selectively internalized the conjugates. Tf-N-AIE was up to 24 times more active than the free drug and showed clear selectivity patterns based on TfR levels. PAI-2-N-AIE showed equivalent activity compared to the parent drug and strong selectivity patterns for uPA levels. In preliminary in vivo experiments, the PAI-2- and Tf-N-AIE conjugates were efficacious at 1/20th and 1/10th of the dose of the free N-AI, respectively, in a metastatic, orthotopic human breast tumor xenograft mouse model. Thus, this strategy specifically delivers and concentrates a novel class of isatin-based, tubulin destabilizing agents to tumors in vivo and warrants further detailed preclinical investigation.
Keywords: Anti-cancer prodrugs, N-alkylisatin, PAI-2/SerpinB2, selective delivery, transferring, bovine serum albumin, mean florescent intensity, mode of action, propidium iodide, receptor mediated endocytosis, quadrupole time of flight
Current Cancer Drug Targets
Title: Targeting Urokinase and the Transferrin Receptor with Novel, Anti-Mitotic N-Alkylisatin Cytotoxin Conjugates Causes Selective Cancer Cell Death and Reduces Tumor Growth
Volume: 12 Issue: 1
Author(s): K. L. Vine, V. Indira Chandran, J. M. Locke, L. Matesic, J. Lee, D. Skropeta, J. B. Bremner and M. Ranson
Affiliation:
Keywords: Anti-cancer prodrugs, N-alkylisatin, PAI-2/SerpinB2, selective delivery, transferring, bovine serum albumin, mean florescent intensity, mode of action, propidium iodide, receptor mediated endocytosis, quadrupole time of flight
Abstract: Tumor-specific delivery of ligand-directed prodrugs can increase the therapeutic window of chemotherapeutics by maintaining efficacy whilst decreasing toxic side effects. We have previously described a series of synthetic Nalkylated isatin cytotoxins that destabilize microtubules and induce apoptosis with 10-fold greater potency than conventional anti-mitotics in vitro. Here, we report the characterization, in vitro cytotoxicity and in vivo efficacy of a lead compound, 5,7-dibromo-N-(p-hydroxymethylbenzyl)isatin (N-AI) conjugated via an esterase-labile linker (N-AIE) to two proven targeting ligands, transferrin (Tf) and plasminogen activator inhibitor type 2 (PAI-2/serpinB2). N-AI was released from N-AIE and the targeting ligands Tf/PAI-2 in an esterase-dependent manner at 37 °C and both Tf- and PAI-2-N-AIE conjugates were stable at physiological pH. Human cancer cell lines which vary in their expression levels of Tf receptor (TfR/CD71) and PAI-2 target, receptor bound urokinase (uPA) selectively internalized the conjugates. Tf-N-AIE was up to 24 times more active than the free drug and showed clear selectivity patterns based on TfR levels. PAI-2-N-AIE showed equivalent activity compared to the parent drug and strong selectivity patterns for uPA levels. In preliminary in vivo experiments, the PAI-2- and Tf-N-AIE conjugates were efficacious at 1/20th and 1/10th of the dose of the free N-AI, respectively, in a metastatic, orthotopic human breast tumor xenograft mouse model. Thus, this strategy specifically delivers and concentrates a novel class of isatin-based, tubulin destabilizing agents to tumors in vivo and warrants further detailed preclinical investigation.
Export Options
About this article
Cite this article as:
L. Vine K., Indira Chandran V., M. Locke J., Matesic L., Lee J., Skropeta D., B. Bremner J. and Ranson M., Targeting Urokinase and the Transferrin Receptor with Novel, Anti-Mitotic N-Alkylisatin Cytotoxin Conjugates Causes Selective Cancer Cell Death and Reduces Tumor Growth, Current Cancer Drug Targets 2012; 12 (1) . https://dx.doi.org/10.2174/156800912798888983
DOI https://dx.doi.org/10.2174/156800912798888983 |
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
-
Beneficial Effects of Traditional Chinese Medicine on the Treatment of Osteoporosis on Ovariectomised Rat Models
Current Drug Targets Highlights in Peptide Nanoparticle Carriers Intended to Oral Diseases
Current Topics in Medicinal Chemistry Titanium Tetrachloride-mediated Synthesis of Diarylmethanes through the Reaction of Benzyl Alcohol Derivatives with Aromatic Substrates
Current Organic Chemistry Imaging of Abdominal Aortic Aneurysm: The Present and the Future
Current Vascular Pharmacology Prodrugs to Codrugs
Current Drug Therapy Research Advances in the Use of Histone Deacetylase Inhibitors for Epigenetic Targeting of Cancer
Current Topics in Medicinal Chemistry The ABC of the Blood-Brain Barrier - Regulation of Drug Efflux Pumps
Current Pharmaceutical Design Molecular Probing and Imaging of Histone Deacetylase Inhibitors in Cancer Treatment
Anti-Cancer Agents in Medicinal Chemistry Single-Cell Sequencing for Drug Discovery and Drug Development
Current Topics in Medicinal Chemistry Development of a Mimotope-Based Vaccine Against CD20 Antigen
Protein & Peptide Letters The Hypothalamus and Obesity
Current Drug Targets Translational Multimodality Neuroimaging
Current Drug Targets Mitochondria as Possible Pharmaceutical Targets for the Effects of Vitamin E and its Homologues in Oxidative Stress-Related Diseases
Current Pharmaceutical Design Suppression of Inflammatory and Allergic Responses by Pharmacologically Potent Fungus Ganoderma lucidum
Recent Patents on Inflammation & Allergy Drug Discovery Free Flap Head and Neck Reconstruction After Cancer Therapy: Current State of the Art
Current Cancer Therapy Reviews Bisphosphonate Anticancer Activity in Multiple Myeloma
Anti-Cancer Agents in Medicinal Chemistry Microwave-assisted Formation of Organic Disulfides of Biochemical Significance
Current Medicinal Chemistry Antitumor Activity of Copper (I)–Nicotinate Complex and Autophagy Modulation in HCC1806 Breast Cancer Cells
Anti-Cancer Agents in Medicinal Chemistry The Mechanism of Calcitriol in Cancer Prevention and Treatment
Current Medicinal Chemistry Pharmacophore Modeling for Antitargets
Current Topics in Medicinal Chemistry