Advancements in the delivery of epigenetic drugs

Abstract

Introduction: Advancements in epigenetic treatments are not only coming from new drugs, but also from modifications or encapsulation of the existing drugs into different formulations leading to greater stability and enhanced delivery to the target site. The epigenome is highly regulated and complex; therefore, it is important that off-target effects of epigenetic drugs be minimized. The step from in vitro to in vivo treatment of these drugs often requires development of a method of effective delivery for clinical translation.

Areas covered: This review covers epigenetic mechanisms such as DNA methylation, chromatin remodeling and small-RNA-mediated gene regulation. There is a section in the review with examples of diseases where epigenetic alterations lead to impaired pathways, with an emphasis on cancer. Epigenetic drugs, their targets and clinical status are presented. Advantages of using a delivery method for epigenetic drugs as well as examples of current advancements and challenges are also discussed.

Expert opinion: Epigenetic drugs have the potential to be very effective therapy against a number of diseases, especially cancers and neurological disorders. As with many chemotherapeutics, undesired side effects need to be minimized. Finding a suitable delivery method means reducing side effects and achieving a higher therapeutic index. Each drug may require a unique delivery method exploiting the drug's chemistry or other physical characteristic requiring interdisciplinary participation and would benefit from a better understanding of the mechanisms of action.

Keywords: RNA; cancer; drug delivery; epidrugs; epigenetics; nanoparticles; prodrugs.

Fig. 1. Example of delivery of epigenetic therapeutics using nanoparticles

Schematic showing two possible mechanisms of epigenetic drugs being delivered via nanoparticles. The nanoparticles are taken into the cell by pinocytosis and enter an endosome. After endosomal escape two different paths are illustrated. The nanoparticle loaded with pre-miR releases its contents in the cytoplasm and is processed by Dicer. Next, it interacts with RISC to either degrade the target mRNA or inhibit its translation. The nanoparticle loaded with HDAC inhibitor drug enters the nucleus and releases the drug. There it blocks the action of HDAC causing an increase in transcription. Abbreviations: pre-miR, precursor miRNA; RISC, RNA-induced silencing complex; HDAC, histone deacetylase inhibitor; TFC, transcription factor complex.

Fig. 2

Hydrodynamic diameter and particle size distribution, and transmission electron microscopic analysis of the decitabine-loaded nanogels formulation. Nanogels are synthesized using a combination of N-isopropylacrylamide (NIPAM), vinyl pyrrolidone (VP), and PEG–maleic anhydride (PEG-MA). NG-70 contains 70% NIPAM, 20% VP and 10% PEG-MA. The ratios of these three polymers were varied and nanogels formed were tested for their physical characteristics and drug loading. Composition of other nanogels is given in original publication. Figure reproduced with permission from Elsevier through RightsLink Copyright Clarence Center [82].

Fig. 3

Antiproliferative effect of decitabine-loaded nanogel in doxorubicin-resistant (MCF-7/Adr) breast cancer cells. a) Comparison of IC₅₀ of decitabine in solution vs. in different nanogel formulations over time. Cells treated with decitabine-nanogel formulations demonstrated sustained antiproliferative effect compared with cells treated with decitabine in solution. Efficacy of DAC nanogel depends on the nanogel composition, with NG-70 showing a more sustained antiproliferative effect than other formulations of nanogels. b) Comparison of IC₅₀ of decitabine in solution vs. decitabine loaded in nanogel (NG-70), depicting the transient antiproliferative effect of decitabine in solution vs. the sustained effect with DAC nanogel. c) Dose-response curves showing the difference in efficacy of decitabine in solution and decitabine in nanogel (NG-70) at 12 d post treatment. Data are expressed as mean ± s.e.m, n = 6 *p ≤ 0.0005, #p ≤ 0.005 DAC solution vs. DAC nanogel. Figure reproduced with permission from Elsevier through RightsLink Copyright Clarence Center [82].