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National Institute of Environmental Health Sciences

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Publication Detail

Title: Enhanced efficacy of combined temozolomide and bromodomain inhibitor therapy for gliomas using targeted nanoparticles.

Authors: Lam, Fred C; Morton, Stephen W; Wyckoff, Jeffrey; Vu Han, Tu-Lan; Hwang, Mun Kyung; Maffa, Amanda; Balkanska-Sinclair, Elena; Yaffe, Michael B; Floyd, Scott R; Hammond, Paula T

Published In Nat Commun, (2018 May 18)

Abstract: Effective treatment for glioblastoma (GBM) is limited by the presence of the blood-brain barrier (BBB) and rapid resistance to single agent therapies. To address these issues, we developed a transferrin-functionalized nanoparticle (Tf-NP) that can deliver dual combination therapies. Using intravital imaging, we show the ability of Tf-NPs to traverse intact BBB in mice as well as achieve direct tumor binding in two intracranial orthotopic models of GBM. Treatment of tumor-bearing mice with Tf-NPs loaded with temozolomide and the bromodomain inhibitor JQ1 leads to increased DNA damage and apoptosis that correlates with a 1.5- to 2-fold decrease in tumor burden and corresponding increase in survival compared to equivalent free-drug dosing. Immunocompetent mice treated with Tf-NP-loaded drugs also show protection from the effects of systemic drug toxicity, demonstrating the preclinical potential of this nanoscale platform to deliver novel combination therapies to gliomas and other central nervous system tumors.

PubMed ID: 29777137 Exiting the NIEHS site

MeSH Terms: Animals; Antineoplastic Agents, Alkylating/chemistry*; Antineoplastic Agents/administration & dosage*; Antineoplastic Agents/chemistry; Apoptosis/drug effects; Azepines/administration & dosage*; Azepines/chemistry; Blood-Brain Barrier/drug effects; Blood-Brain Barrier/metabolism; Brain Neoplasms/drug therapy*; Brain Neoplasms/metabolism; Brain Neoplasms/physiopathology; Cell Line, Tumor; Drug Delivery Systems/instrumentation; Drug Delivery Systems/methods*; Glioma/drug therapy*; Glioma/metabolism; Glioma/physiopathology; Humans; Male; Mice; Mice, Inbred C57BL; Nanoparticles/chemistry*; Temozolomide/administration & dosage*; Temozolomide/chemistry; Triazoles/administration & dosage*; Triazoles/chemistry; Xenograft Model Antitumor Assays

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