Nanoparticle formulations of histone deacetylase inhibitors for effective chemoradiotherapy in solid tumors

Edina C Wang; Yuanzeng Min; Robert C Palm; James J Fiordalisi; Kyle T Wagner; Nabeel Hyder; Adrienne D Cox; Joseph M Caster; Xi Tian; Andrew Z Wang

doi:10.1016/j.biomaterials.2015.02.015

Nanoparticle formulations of histone deacetylase inhibitors for effective chemoradiotherapy in solid tumors

Biomaterials. 2015 May:51:208-215. doi: 10.1016/j.biomaterials.2015.02.015. Epub 2015 Feb 19.

Authors

Affiliations

¹ Laboratory of Nano- and Translational Medicine, Lineberger Comprehensive Cancer Center, Carolina Center for Cancer Nanotechnology Excellence, Carolina Institute of Nanomedicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Radiation Oncology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
² Department of Radiation Oncology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
³ Laboratory of Nano- and Translational Medicine, Lineberger Comprehensive Cancer Center, Carolina Center for Cancer Nanotechnology Excellence, Carolina Institute of Nanomedicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
⁴ Laboratory of Nano- and Translational Medicine, Lineberger Comprehensive Cancer Center, Carolina Center for Cancer Nanotechnology Excellence, Carolina Institute of Nanomedicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Radiation Oncology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. Electronic address: zawang@med.unc.edu.

Abstract

Histone deacetylase inhibitors (HDACIs) represent a class of promising agents that can improve radiotherapy in cancer treatment. However, the full therapeutic potential of HDACIs as radiosensitizers has been restricted by limited efficacy in solid malignancies. In this study, we report the development of nanoparticle (NP) formulations of HDACIs that overcome these limitations, illustrating their utility to improve the therapeutic ratio of the clinically established first generation HDACI vorinostat and a novel second generation HDACI quisinostat. We demonstrate that NP HDACIs are potent radiosensitizers in vitro and are more effective as radiosensitizers than small molecule HDACIs in vivo using mouse xenograft models of colorectal and prostate carcinomas. We found that NP HDACIs enhance the response of tumor cells to radiation through the prolongation of γ-H2AX foci. Our work illustrates an effective method for improving cancer radiotherapy treatment.

Keywords: Chemotherapy; Controlled drug release; Drug delivery; Nanoparticle.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Animals
Cell Line, Tumor
Chemistry, Pharmaceutical
Chemoradiotherapy*
Histone Deacetylase Inhibitors / pharmacology
Histone Deacetylase Inhibitors / therapeutic use*
Histones / metabolism
Humans
Hydroxamic Acids / pharmacology
Hydroxamic Acids / therapeutic use
Male
Mice, Nude
Nanoparticles / chemistry*
Nanoparticles / ultrastructure
Neoplasms / pathology
Neoplasms / therapy*
Radiation-Sensitizing Agents / pharmacology
Radiation-Sensitizing Agents / therapeutic use
Vorinostat

Substances

H2AX protein, human
Histone Deacetylase Inhibitors
Histones
Hydroxamic Acids
Radiation-Sensitizing Agents
Vorinostat

Abstract

Publication types

MeSH terms

Substances

Grants and funding