Advances in the Delivery and Development of Epigenetic Therapeutics for the Treatment of Cancer

Abstract

Gene expression at the transcriptional level is altered by epigenetic modifications such as DNA methylation, histone methylation, and acetylation, which can upregulate, downregulate, or entirely silence genes. Pathological dysregulation of epigenetic processes can result in the development of cancer, neurological problems, metabolic disorders, and cardiovascular diseases. It is of promising therapeutic interest to find medications that target these epigenetic alterations. Despite the enormous amount of work that has been done in this area, very few molecules have been approved for clinical purposes. This article provides a comprehensive review of recent advances in epigenetic therapeutics for cancer, with a specific focus on emerging delivery and development strategies. Various delivery systems, including prodrugs, conjugated molecules, nanoparticles (NPs), and liposomes, as well as remedial strategies such as combination therapies, and epigenetic editing, are being investigated to improve the efficacy and specificity of epigenetic drugs (epi-drugs). Furthermore, the challenges associated with available epi-drugs and the limitations of their translation into clinics have been discussed. Target selection, isoform selectivity, physiochemical properties of synthesized molecules, drug screening, and scalability of epi-drugs from preclinical to clinical fields are the major shortcomings that are addressed. This Review discusses novel strategies for the identification of new biomarkers, exploration of the medicinal chemistry of epigenetic modifiers, optimization of the dosage regimen, and design of proper clinical trials that will lead to better utilization of epigenetic modifiers over conventional therapies. The integration of these approaches holds great potential for improving the efficacy and precision of epigenetic treatments, ultimately benefiting cancer patients.

First‐Principles Design of Alloy Systems, Part I: Effects of Solute Type, Concentration, and Distribution on Alloying and Mechanical Properties – As‐Quenched Dilute Al (Mg, Si) Alloys

“…The highest frequencies illustrate the most common distances ( d eq for d equilibrium ) between the 1NN solute atoms. That is, for the two most dilute alloys, the differences are consistent with the field effect principally from the electronegativities but also, to a lesser extent, the sizes and valences of the atoms, where the electronegativities for Si (4+, ≈0.115 nm [ 83 ] ) is 1.90 [ 84 ] and that for Mg (2+, ≈0.167 nm [ 83 ] ) is 1.31. [ 84 ] The electronegativity of the matrix Al (3+, ≈0.136 nm [ 83 ] ) is 1.61.…”

“…That is, for the two most dilute alloys, the differences are consistent with the field effect principally from the electronegativities but also, to a lesser extent, the sizes and valences of the atoms, where the electronegativities for Si (4+, ≈0.115 nm [ 83 ] ) is 1.90 [ 84 ] and that for Mg (2+, ≈0.167 nm [ 83 ] ) is 1.31. [ 84 ] The electronegativity of the matrix Al (3+, ≈0.136 nm [ 83 ] ) is 1.61. [ 84 ] The pervasive role of electronegativity is implicit in that increasing electronegativity induces a net positive charge, thereby enhancing the polarity conducive to solubility in an inevitably polar lattice.…”

“…It would be expected that there also would be an atomic size effect , where the metallic radii for Si (0.115 nm) [ 83 ] and Mg (0.167 nm [ 83 ] ) would introduce a physical approach limitation based on the tendency to recrystallize Mg 2 Si (β), which would occur only at extremely high alloy concentrations. This is likely to come into play only at higher alloying concentrations as these distances are significantly less than the d eq the (0.75–0.92 nm) normalized by the efficiency of the APT of 57 % (0.42–1.61 nm).…”