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. 2021 Oct 19;13(10):1728.
doi: 10.3390/pharmaceutics13101728.

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

Athika Darumas Putri  1 , Pai-Shan Chen  2 , Yu-Lin Su  1 , Jia-Pei Lin  1 , Jing-Ping Liou  1 , Chien-Ming Hsieh  1
Affiliations

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

Athika Darumas Putri et al. Pharmaceutics. .

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.

Keywords: MPT0B291; albumin nanoparticle; high-pressure homogenizer; histone deacetylase.

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Conflict of interest statement

The authors declare no conflict of interest. The funder had no role in the design of the study, in the collection, analyses or interpretation of data, in the writing of the manuscript, or in the decision to publish the results.

Figures

Figure 1
Figure 1
Chemical structure of MPT0B291, with molecular weight 343.36 g/mol.
Figure 2
Figure 2
Effects of different amplitudes (AMPLs) of ultrasonication and different cycles of high-pressure homogenization on the particle size and size distribution. Column: particle size (nm); line: polydispersity index. Each point represents the mean ± SD. Error bars represent the standard deviation (n = 3).
Figure 3
Figure 3
Effects of different pressures of high-pressure homogenization at different cycles on the particle size and size distribution. Column: particle size (nm); line: polydispersity index. Each point represents the mean ± SD. Error bars represent the standard deviation (n = 3).
Figure 4
Figure 4
Effects of different ratios of the dispersed phase (DP) and continuous phase (CP) and different cycles of high-pressure homogenization on the particle size and size distribution. Column: particle size (nm); line: polydispersity index. Each point represents the mean ± SD. Error bars represent the standard deviation (n = 3).
Figure 5
Figure 5
Transmission electron microscopic (TEM) images of MPT0B291-human serum albumin (HSA) nanoparticles (NPs). Scale bars represent 100 (a) and 200 nm (b).
Figure 6
Figure 6
Particle size and size distribution of MPT0B291-human serum albumin (HSA) nanoparticles (NPs) stored at 4 °C for 4 weeks after reconstitution. Each point represents the mean ± SD. Error bars represent the standard deviation (n = 3).
Figure 7
Figure 7
In vitro drug-release profiles of free MPT0B291 and MPT0B291-human serum albumin (HSA) nanoparticles (NPs) in pH 7.4 phosphate buffer containing 1% Tween 80 at 37 °C. Data shown are the mean ± SD (n = 3). * p < 0.0001 when free MPT0B291 was compared to MPT0B291-HSA NPs at 8 h.
Figure 8
Figure 8
Cell viability of blank human serum albumin (HSA) nanoparticles (NPs) in Mia Paca-2 cells (a) and comparison of the cell viability of free MPT0B291 and MPT0B291-HSA NPs in Mia Paca-2 cells (b). Each point represents the mean ± SD. Error bars represent the standard deviation (n = 3).
Figure 9
Figure 9
Determination of the maximum tolerated dose (MTD) of MPT0B291 and MPT0B291-human serum albumin (HSA) nanoparticles (NPs) in mice. Body weight changes and survival rates of female BALB/c mice after single-dose intravenous administration with 50, 75 and 150 mg/kg of MPT0B291 solution (a,b) and with 50, 75, 150 and 200 mg/kg of MPT0B291-HSA NPs (c,d), respectively. Each point represents the mean ± SD. Error bars represent the standard deviation (n = 4).
Figure 10
Figure 10
Plasma concentration-time curves of MPT0B291 after intravenous administration with MPT0B291-human serum albumin (HSA) nanoparticles (NPs) and an MPT0B291 solution (at a single dose of 5 mg/kg body weight) to rats. Each point represents the mean ± SD of three determinations (n = 4).
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