First In Vivo Testing of Compounds Targeting Group 3 Medulloblastomas Using an Implantable Microdevice as a New Paradigm for Drug Development. J Biomed Nanotechnol 2016 Jun;12(6):1297-302
Date
06/21/2016Pubmed ID
27319222Pubmed Central ID
PMC5293728DOI
10.1166/jbn.2016.2262Scopus ID
2-s2.0-84964758617 (requires institutional sign-in at Scopus site) 38 CitationsAbstract
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.
Author List
Jonas O, Calligaris D, Methuku KR, Poe MM, Francois JP, Tranghese F, Changelian A, Sieghart W, Ernst M, Krummel DA, Cook JM, Pomeroy SL, Cima M, Agar NY, Langer R, Sengupta SAuthor
James M. Cook PhD University Distinguished Professor in the Chemistry and Biochemistry department at University of Wisconsin - MilwaukeeMESH terms used to index this publication - Major topics in bold
AnimalsAntineoplastic Agents
Benzodiazepines
Cell Line, Tumor
Cerebellar Neoplasms
Drug Delivery Systems
Female
Humans
Medulloblastoma
Mice
Mice, Nude
Molecular Imaging
Prostheses and Implants
Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
