Design and Evaluation of Tumor‐Specific Dendrimer Epigenetic Therapeutics

ChemistryOpen

Dr. Hong Zong¹  Dhavan Shah¹  Katherine Selwa¹  Ryan E. Tsuchida¹  Dr. Rahul Rattan¹  Jay Mohan¹  Dr. Adam B. Stein²  James B. Otis¹ 

[1] Michigan Nanotechnology Institute for Medicine and Biological Sciences, University of Michigan, Room 9220C MSRBIII, Ann Arbor, MI, USA);Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, CVC Room 2547, Ann Arbor, MI, USA)

关键词: cancer;    dendrimers;    epigenetics;    histone deacetylase (HDAC) inhibitors;    nanoparticles;   

DOI  :  10.1002/open.201402141

来源: Wiley

【 摘 要 】

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.

【 授权许可】

CC BY-NC-ND   
© 2015 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.

Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.