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.Targeting tumors via epigenetics: Histone deacetylase inhibitors (HDACi) alter the epigenetic state of tumors and are promising therapeutics for cancer. Although studies with HDACi have shown promise in some cancers, variable efficacy and off‐target effects have limited their use. Here we report the design and evaluation of a tumor‐specific dendrimer–HDACi.