First In Vivo Testing of Compounds Targeting Group 3 Medulloblastomas Using an Implantable Microdevice as a New Paradigm for Drug Development
| Autor: | Margot Ernst, Werner Sieghart, Nathalie Y. R. Agar, Kashi Reddy Methuku, Robert Langer, Oliver Jonas, Michael M. Poe, Armen Changelian, Soma Sengupta, Michael J. Cima, Jessica Pierre Francois, Daniel Pomeranz Krummel, Frank Tranghese, Scott L. Pomeroy, David Calligaris, James M. Cook |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Drug media_common.quotation_subject Biomedical Engineering Mice Nude Pharmaceutical Science Medicine (miscellaneous) Antineoplastic Agents Bioengineering Biology Pharmacology Article Efficacy Benzodiazepines Mice 03 medical and health sciences Drug Delivery Systems 0302 clinical medicine In vivo Cell Line Tumor medicine Animals Humans General Materials Science Cerebellar Neoplasms media_common Medulloblastoma Tumor microenvironment GABAA receptor Prostheses and Implants medicine.disease Molecular Imaging 030104 developmental biology Drug development Spectrometry Mass Matrix-Assisted Laser Desorption-Ionization 030220 oncology & carcinogenesis Drug delivery Female |
| Zdroj: | Journal of Biomedical Nanotechnology. 12:1297-1302 |
| ISSN: | 1550-7033 |
| DOI: | 10.1166/jbn.2016.2262 |
| Popis: | Medulloblastoma is the most common childhood malignant brain tumor. The most lethal medulloblastoma subtype exhibits a high expression of the GABAA receptor α5 subunit gene and MYC amplification. New benzodiazepines have been synthesized to function as α5-GABAA receptor ligands. To compare their efficacy with that of standard-of-care treatments, we have employed a newly developed microscale implantable device that allows for high-throughput localized intratumor drug delivery and efficacy testing. Microdoses of each drug were delivered into small distinct regions of tumors, as confirmed by tissue mass spectrometry, and the local drug effect was determined by immunohistochemistry. We have identified a benzodiazepine derivative, KRM-II-08, as a new potent inhibitor in several α5-GABAA receptor expressing tumor models. This is the first instance of in vivo testing of several benzodiazepine derivatives and standard chemotherapeutic drugs within the same tumor. Obtaining high-throughput drug efficacy data within a native tumor microenvironment as detailed herein, prior to pharmacological optimization for bioavailability or safety and without systemic exposure or toxicity, may allow for rapid prioritization of drug candidates for further pharmacological optimization. |
| Databáze: | OpenAIRE |
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