Optimization and Development of Selective Histone Deacetylase Inhibitor (MPT0B291)-Loaded Albumin Nanoparticles for Anticancer Therapy.

Athika Darumas Putri,Jing-Ping Liou,Jia-Pei Lin,Chien-Ming Hsieh,Yu-Lin Su,Pai-Shan Chen

doi:10.3390/pharmaceutics13101728

Athika Darumas Putri, Jing-Ping Liou + Show 4 more

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https://doi.org/10.3390/pharmaceutics13101728

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Abstract

Histone deacetylase (HDAC) inhibitors have emerged as a new class of antitumor agent for various types of tumors. MPT0B291, a novel selective inhibitor of HDAC6, demonstrated significant antiproliferative activity in various human cancer cell types. However, MPT0B291 has very low water solubility, which limits its clinical use for cancer therapy. In the current study, MPT0B291 was encapsulated in human serum albumin (HSA), and its anticancer activities were investigated. Nanoparticles (NPs) were prepared using two-stage emulsification resulting in 100~200-nm NPs with a fine size distribution (polydispersity index of <0.3). The in vitro drug release profiles of MPT0B291-loaded HSA NPs presented sustained-release properties. The cytotoxic effect on MIA PaCa-2 human pancreatic carcinoma cells was found to be similar to MPT0B291-loaded HSA NPs and the free-drug group. The albumin-based formulation provided a higher maximum tolerated dose than that of a drug solution with reduced toxicity toward normal cells. Furthermore, in vivo pharmacokinetic studies demonstrated an effective increase (5~8-fold) in the bioavailability of NPs containing MPT0B291 loaded in HSA compared to the free-drug solution with an extended circulation time (t1/2) leading to significantly enhanced efficacy of anticancer treatment.

Highlights

Histone acetyltransferases (HATs) and histone deacetylases (HDACs) are known to simultaneously regulate both intracellular and extracellular responses toward epigenetic modifications by respectively executing the acetylation and deacetylation of lysine residues at the amino terminals of histones [1,2]
It is important to note that using a higher albumin concentration for preparation of albumin NPs would be anticipated to higher albumin concentration for preparation of albumin NPs would be anticipated to initiate higher levels of disulfide bonds formation leading to increased particle size and a initiate higher levels of disulfide bonds formation leading to increased particle size and ofof protein aggregation
We demonstrated that MPT0B291, a waterinsoluble anticancer drug, could be successfully loaded into albumin NPs via a two-stage emulsification method under optimized conditions

Summary

Introduction

Histone acetyltransferases (HATs) and histone deacetylases (HDACs) are known to simultaneously regulate both intracellular and extracellular responses toward epigenetic modifications by respectively executing the acetylation and deacetylation of lysine residues at the amino terminals of histones [1,2]. Overexpression and atypical recruitment of HDACs for acetyl-group removal that occurs at their promoter sites raises the possibility of an imbalance in acetylation-deacetylation processes [3,4,5]. Aberrant deacetylation due to the HDAC mechanism was found in non-histone proteins, such as p53, which initiated a mutation of p53 [6]. Targeting HDACs is considered an important strategy in developing anticancer agents. Inhibition of HDACs has garnered potential interest in anticancer development as it induces cell-cycle arrest and cell apoptosis, and decreases cancer metastasis [7]. Several recently developed HDAC inhibitors, such as deacetylase-trichostatin A (TSA) and deacetylase-suberoylanilide hydroxamic acid (SAHA), showed excellent results in suppressing cancer cell growth [8,9,10]

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