title: Design and Evaluation of Tumor-Specific Dendrimer Epigenetic Therapeutics.
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.
authors.affiliation: Michigan Nanotechnology Institute for Medicine and Biological Sciences, University of Michigan, Room 9220C MSRBIII 1150 W. Medical Center Drive, Ann Arbor, MI, 48109, USA).
authors.forename: Hong
authors.initials: H
authors.lastname: Zong
authors.affiliation: Michigan Nanotechnology Institute for Medicine and Biological Sciences, University of Michigan, Room 9220C MSRBIII 1150 W. Medical Center Drive, Ann Arbor, MI, 48109, USA).
authors.forename: Dhavan
authors.initials: D
authors.lastname: Shah
authors.affiliation: Michigan Nanotechnology Institute for Medicine and Biological Sciences, University of Michigan, Room 9220C MSRBIII 1150 W. Medical Center Drive, Ann Arbor, MI, 48109, USA).
authors.forename: Katherine
authors.initials: K
authors.lastname: Selwa
authors.affiliation: Michigan Nanotechnology Institute for Medicine and Biological Sciences, University of Michigan, Room 9220C MSRBIII 1150 W. Medical Center Drive, Ann Arbor, MI, 48109, USA).
authors.forename: Ryan E
authors.initials: RE
authors.lastname: Tsuchida
authors.affiliation: Michigan Nanotechnology Institute for Medicine and Biological Sciences, University of Michigan, Room 9220C MSRBIII 1150 W. Medical Center Drive, Ann Arbor, MI, 48109, USA).
authors.forename: Rahul
authors.initials: R
authors.lastname: Rattan
authors.affiliation: Michigan Nanotechnology Institute for Medicine and Biological Sciences, University of Michigan, Room 9220C MSRBIII 1150 W. Medical Center Drive, Ann Arbor, MI, 48109, USA).
authors.forename: Jay
authors.initials: J
authors.lastname: Mohan
authors.affiliation: Department 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).
authors.forename: Adam B
authors.initials: AB
authors.lastname: Stein
authors.affiliation: Michigan Nanotechnology Institute for Medicine and Biological Sciences, University of Michigan, Room 9220C MSRBIII 1150 W. Medical Center Drive, Ann Arbor, MI, 48109, USA).
authors.forename: James B
authors.initials: JB
authors.lastname: Otis
authors.affiliation: Department 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) ; Michigan Nanotechnology Institute for Medicine and Biological Sciences, University of Michigan, Room 9220C MSRBIII 1150 W. Medical Center Drive, Ann Arbor, MI, 48109, USA).
authors.forename: Sascha N
authors.initials: SN
authors.lastname: Goonewardena
keywords: cancer; dendrimers; epigenetics; histone deacetylase (HDAC) inhibitors; nanoparticles