Histone Deacetylase Inhibitor (HDACi) Conjugated Polycaprolactone for Combination Cancer Therapy

Abstract

The short chain fatty acid, 4-phenylbutyric acid (PBA), is used for the treatment of urea cycle disorders and sickle cell disease as an endoplasmic reticulum stress inhibitor. PBA is also known as a histone deacetylase inhibitor (HDACi). We report here the effect of combination therapy on HeLa cancer cells using PBA as the HDACi together with the anticancer drug, doxorubicin (DOX). We synthesized γ-4-phenylbutyrate–ε-caprolactone monomer which was polymerized to form poly(γ-4-phenylbutyrate–ε-caprolactone) (PPBCL) homopolymer using NdCl3·3TEP/TIBA (TEP = triethyl phosphate, TIBA = triisobutylaluminum) catalytic system. DOX-loaded nanoparticles were prepared from the PPBCL homopolymer using poly(ethylene glycol) as a surfactant. An encapsulation efficiency as high as 88% was obtained for these nanoparticles. The DOX-loaded nanoparticles showed a cumulative release of >95% of DOX at pH 5 and 37 °C within 12 h, and PBA release was monitored by 1H NMR spectroscopy. The efficiency of the combination therapy can notably be seen in the cytotoxicity study carried out on HeLa cells, where only ~20% of cell viability was observed after treatment with the DOX-loaded nanoparticles. This drastic cytotoxic effect on HeLa cells is the result of the dual action of DOX and PBA on the DNA strands and the HDAC enzymes, respectively. Overall, this study shows the potential of combination treatment with HDACi and DOX anticancer drug as compared to the treatment with an anticancer drug alone.

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“…Due to its deficient biological activity and hydrophobicity it is widely used in absorbable suture materials, surgical dressing, and internal fixations. [30][31][32] It is also approved by the United States Food and Drug Administration (FDA). The popularity of PCL in these applications can be attributed to its biocompatibility, biodegradability, and high processability.…”

Nanomedicine to Overcome Multidrug Resistance Mechanisms in Colon and Pancreatic Cancer: Recent Progress

“…In addition, other HDAC inhibitors, such as vorinostat and quisinostat, were associated with PLGA-lecithin-PEG NPs to increase the radiosensitization of these tumors [ 164 ]. More recently, Kularatne, et al [ 165 ]) developed polycaprolactone polymer NPs associated with 4-phenylbutyric acid, an HDAC inhibitor, to enhance DOX-based therapy in CRC, while Busi, et al [ 166 ] developed keratin NPs loaded with 9-hydroxystearic acid, another HDAC1 inhibitor, which induced cell cycle arrest and cell death in CRC lines.…”

Nanotechnology-Based Histone Deacetylase Inhibitors for Cancer Therapy

“…(B) Active targeting: the scheme of dual-targeted liposome system co-loading gefitinib and vorinostat and targeting HER-2 expressed tumor cells and mannose receptor expressed TAMs, its anti-tumor effect on H1975 tumor mouse model, and the accumulation by in vivo imaging study (Peng et al, 2017). (C) Stimuli-responsive controlled drug release: the illustration of pH-responsive DOX loading nanoparticles by the self-assembling of PBA conjugated polycaprolactone, and the drug release in response to different pH (Kularatne et al, 2018). (D) Combination therapy: the scheme of vorinostat-containing nanoparticles for sensitizing radiotherapy (Jiang et al, 2018).…”