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Nat Commun. 2018 May 18;9(1):1991. doi: 10.1038/s41467-018-04315-4.

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

Author information

1
Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.
2
Center for Precision Cancer Medicine, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.
3
Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.
4
Marble Center for Cancer Nanomedicine, Massachusetts Institute of Technology, Cambrige, MA, 02139, USA.
5
Department of Radiation Oncology, Duke University School of Medicine, Durham, NC, 27710, USA.
6
Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, 27710, USA.
7
Departments of Biology and Bioengineering, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.
8
Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA.
9
Department of Radiation Oncology, Duke University School of Medicine, Durham, NC, 27710, USA. scott.floyd@dm.duke.edu.
10
Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, 27710, USA. scott.floyd@dm.duke.edu.
11
Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA. hammond@mit.edu.
12
Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA. hammond@mit.edu.
13
Marble Center for Cancer Nanomedicine, Massachusetts Institute of Technology, Cambrige, MA, 02139, USA. hammond@mit.edu.

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.

PMID:
29777137
PMCID:
PMC5959860
DOI:
10.1038/s41467-018-04315-4
[Indexed for MEDLINE]
Free PMC Article

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