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

Fred C. Lam, Stephen W. Morton, Jeffrey Wyckoff, Tu-Lan Han, Mun Kyung Hwang, Amanda Maffa, Elena Balkanska-Sinclair, Michael B Yaffe, Scott R Floyd () and Paula T Hammond ()
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Fred C. Lam: Massachusetts Institute of Technology
Stephen W. Morton: Massachusetts Institute of Technology
Jeffrey Wyckoff: Massachusetts Institute of Technology
Tu-Lan Han: Massachusetts Institute of Technology
Mun Kyung Hwang: Massachusetts Institute of Technology
Amanda Maffa: Massachusetts Institute of Technology
Elena Balkanska-Sinclair: Duke University School of Medicine
Michael B Yaffe: Massachusetts Institute of Technology
Scott R Floyd: Duke University School of Medicine
Paula T Hammond: Massachusetts Institute of Technology

Nature Communications, 2018, vol. 9, issue 1, 1-11

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-04315-4

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