Enhanced efficacy of combined temozolomide and bromodomain inhibitor therapy for gliomas using targeted nanoparticles.
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2018-05-18
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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.
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Lam, Fred C, Stephen W Morton, Jeffrey Wyckoff, Tu-Lan Vu Han, Mun Kyung Hwang, Amanda Maffa, Elena Balkanska-Sinclair, Michael B Yaffe, et al. (2018). Enhanced efficacy of combined temozolomide and bromodomain inhibitor therapy for gliomas using targeted nanoparticles. Nature communications, 9(1). 10.1038/s41467-018-04315-4 Retrieved from https://hdl.handle.net/10161/17087.
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Scott Richard Floyd
Diseases of the brain carry particular morbidity and mortality, given the fundamental function of the brain for human life and quality of life. Disease of the brain are also particularly difficult to study, given the complexity of the brain. Model systems that capture this complexity, but still allow for experiments to test therapies and mechanisms of disease are badly needed. We have developed an experimental model system that uses slices made from rat and mouse brains to create a test platform to research new treatments for brain diseases such as stroke, Alzheimer's disease, Huntington's disease and brain tumors. This model system reduces the number of experimental animals used, and streamlines experiments so that final testing in laboratory animals is more efficient. We use this brainslice system and limited numbers of experimental animals to test drugs and genetic pathways to treat stroke, Alzheimer's disease, Huntington's disease and brain tumors. As many brain tumors are treated with radiation therapy, we have a particular interest in the cellular response to DNA damage caused by radiation. DNA damage signaling and repair are fundamental processes necessary for cells to maintain genomic integrity. Problems with these processes can lead to cancer. As many cancer cells have altered DNA damage and repair pathways, we can apply DNA damage as cancer therapy. Our knowledge of how normal and neoplastic cells handle DNA damage is still incomplete. A deeper understanding can lead to improved cancer treatment, and to better protection from the harmful effects of DNA damaging agents like radiation. To this end, we plan experiments that test the effects of radiation on normal animal tissues and animal models of cancer, as well as molecular pathways in brain diseases such as Alzheimer’s, Huntington’s and stroke.
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