Design and Evaluation of Tumor-Specific Dendrimer Epigenetic Therapeutics |
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Authors: | Dr. Hong Zong Dhavan Shah Katherine Selwa Ryan E Tsuchida Dr. Rahul Rattan Jay Mohan Dr. Adam B Stein James B Otis Dr. Sascha N Goonewardena |
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Affiliation: | aDepartment of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, CVC Room 2547, 1500 E. Medical Center Drive, SPC 5853, Ann Arbor, MI, 48109-5853, USA);bMichigan Nanotechnology Institute for Medicine and Biological Sciences, University of Michigan, Room 9220C MSRBIII, 1150 W. Medical Center Drive, Ann Arbor, MI, 48109, USA) |
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Abstract: | Histone deacetylase inhibitors (HDACi) are promising therapeutics for cancer. HDACi alter the epigenetic state of tumors and provide a unique approach to treat cancer. Although studies with HDACi have shown promise in some cancers, variable efficacy and off-target effects have limited their use. To overcome some of the challenges of traditional HDACi, we sought to use a tumor-specific dendrimer scaffold to deliver HDACi directly to cancer cells. Here we report the design and evaluation of tumor-specific dendrimer–HDACi conjugates. The HDACi was conjugated to the dendrimer using an ester linkage through its hydroxamic acid group, inactivating the HDACi until it is released from the dendrimer. Using a cancer cell model, we demonstrate the functionality of the tumor-specific dendrimer–HDACi conjugates. Furthermore, we demonstrate that unlike traditional HDACi, dendrimer–HDACi conjugates do not affect tumor-associated macrophages, a recently recognized mechanism through which drug resistance emerges. We anticipate that this new class of cell-specific epigenetic therapeutics will have tremendous potential in the treatment of cancer. |
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Keywords: | cancer dendrimers epigenetics histone deacetylase (HDAC) inhibitors nanoparticles |
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