Antitumour activity and tolerability of an EphA2-targeted nanotherapeutic in multiple mouse models
| Autor: | Lia Luus, Vasileios Askoxylakis, John Wilton, Alexey Lugovskoy, Kenneth J. Olivier, Stephanie Grabow, Jaeyeon Kim, Christine Pien, Geoffrey Kuesters, Suresh K. Tipparaju, Melissa Geddie, Nancy Dumont, Mark E. Hayes, Alexander Koshkaryev, Sarah A Schihl, C. Patrick Reynolds, Rachel Blaydes, Andrew J. Sawyer, James D. Marks, Tad Kornaga, James Suchy, Charles O. Noble, Dmitri B. Kirpotin, Shinji Oyama, Neeraj Kohli, Zhaohua Richard Huang, Walid S. Kamoun, Daryl C. Drummond, Yu Zhou |
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| Rok vydání: | 2019 |
| Předmět: |
Bridged-Ring Compounds
0301 basic medicine Drug media_common.quotation_subject medicine.medical_treatment Biomedical Engineering Medicine (miscellaneous) Antineoplastic Agents Bioengineering Docetaxel Mice SCID Pharmacology Neutropenia 03 medical and health sciences 0302 clinical medicine Mice Inbred NOD Cell Line Tumor medicine Animals Humans Tissue Distribution Cell Proliferation media_common Liposome Chemotherapy business.industry Receptor EphA2 Prodrug medicine.disease Xenograft Model Antitumor Assays Tumor Burden Computer Science Applications Disease Models Animal 030104 developmental biology Tolerability Liposomes Toxicity Nanoparticles Taxoids business 030217 neurology & neurosurgery Biotechnology medicine.drug |
| Zdroj: | Nature Biomedical Engineering. 3:264-280 |
| ISSN: | 2157-846X |
| Popis: | Antibody-mediated tumour targeting and nanoparticle-mediated encapsulation can reduce the toxicity of antitumour drugs and improve their efficacy. Here, we describe the performance of a nanotherapeutic encapsulating a hydrolytically sensitive docetaxel prodrug and conjugated to an antibody specific for EphA2-a receptor overexpressed in many tumours. Administration of the nanotherapeutic in mice led to slow and sustained release of the prodrug, reduced exposure of active docetaxel in the circulation (compared with administration of the free drug) and maintenance of optimal exposure of the drug in tumour tissue. We also show that administration of the nanotherapeutic in rats and dogs resulted in minimal haematological toxicity, as well as the absence of neutropenia and improved overall tolerability in multiple rodent models. Targeting of the nanotherapeutic to EphA2 improved tumour penetration and resulted in markedly enhanced antitumour activity (compared with administration of free docetaxel and non-targeted nanotherapeutic controls) in multiple tumour-xenografted mice. This nanomedicine could become a potent and safe therapeutic alternative for cancer patients undergoing chemotherapy. |
| Databáze: | OpenAIRE |
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