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Updated: Jun 11, 2026
Assays for Validating Histone Acetyltransferase Inhibitors
Published on: August 6, 2020
Liposomes loaded with histone deacetylase inhibitors for breast cancer therapy
Giorgia Urbinati1, Véronique Marsaud, Vincent Plassat
1Centre National de la Recherche Scientifique, UMR 8612, Faculté de Pharmacie, 5 rue J.B. Clément, Châtenay-Malabry, F-92296, France.
Abstract:
Histone deacetylase (HDAC) inhibitors (HDACi) of the class I trichostatin A (TSA), CG1521 (CG), and PXD101 (PXD) were incorporated at a high rate (approximately 1mM) in liposomes made of egg phosphatidylcholine/cholesterol/distearoylphosphoethanolamine-polyethylenglycol(2000) (64:30:6). Physicochemical parameters (size, zeta potential, loading, stability, release kinetics) of these HDACi-loaded pegylated liposomes were optimized and their cytotoxicity (MTT test) was measured in MCF-7, T47-D, MDA-MB-231 and SkBr3 breast cancer cell lines. In MCF-7 cells, TSA and PXD were efficient inducers of proteasome-mediated estradiol receptor alpha degradation and they both affected estradiol-induced transcription (TSA>PXD) contrary to CG. Moreover, TSA most efficiently altered breast cancer cell viability as compared to the free drug, CG-liposomes being the weakest, while unloaded liposomes had nearly no cytotoxicity. Pegylated liposomes loaded with TSA or PXD remained stable in size, charge and biological activity for one month when stored at 4 degrees C. All HDACi-loaded liposomes released slowly the encapsulated drug in vitro, CG-loaded liposomes showed the slowest release kinetic. These formulations could improve the efficacy of HDACi not only in breast cancers but also in other solid tumors because most of these drugs are poor water soluble and unstable in vivo, and their administration remains a challenge.
Insights
Pegylated liposomes effectively delivered histone deacetylase inhibitors (HDACi) like trichostatin A (TSA) and PXD101, enhancing breast cancer cell death. These stable formulations show promise for improving HDACi therapy in solid tumors.
Area of Science:
- Nanomedicine
- Cancer Therapeutics
- Pharmacology
Background:
- Histone deacetylase inhibitors (HDACi) face challenges in water solubility and in vivo stability, limiting their therapeutic application.
- Class I HDACi, including trichostatin A (TSA), CG1521 (CG), and PXD101 (PXD), are potent anticancer agents.
- Developing effective drug delivery systems is crucial for overcoming the limitations of HDACi administration.
Purpose of the Study:
- To develop and characterize pegylated liposomes loaded with class I HDAC inhibitors (TSA, CG, PXD).
- To evaluate the physicochemical properties, stability, and in vitro cytotoxicity of these novel HDACi-loaded liposomes in breast cancer cell lines.
- To assess the impact of HDACi-loaded liposomes on proteasome-mediated degradation and gene transcription in cancer cells.
Main Methods:
- Incorporation of TSA, CG, and PXD into pegylated liposomes composed of egg phosphatidylcholine/cholesterol/distearoylphosphoethanolamine-polyethylenglycol(2000).
- Optimization of liposome physicochemical parameters including size, zeta potential, drug loading, stability, and release kinetics.
- Cytotoxicity assessment using the MTT assay on MCF-7, T47-D, MDA-MB-231, and SkBr3 breast cancer cell lines.
Main Results:
- Pegylated liposomes demonstrated optimal physicochemical properties and stability for at least one month at 4°C.
- TSA and PXD effectively induced proteasome-mediated degradation of estrogen receptor alpha and affected estradiol-induced transcription in MCF-7 cells.
- TSA-loaded liposomes showed the highest efficacy in reducing breast cancer cell viability, while CG-liposomes were least effective; unloaded liposomes exhibited minimal cytotoxicity.
- All HDACi-loaded liposomes exhibited slow in vitro drug release, with CG-loaded liposomes showing the slowest kinetics.
Conclusions:
- Pegylated liposomes provide a promising formulation strategy for improving the delivery and efficacy of poorly soluble and unstable HDAC inhibitors.
- These liposomal HDACi formulations have the potential to enhance therapeutic outcomes in breast cancer and other solid tumors.
- The study highlights the potential of nanomedicine in overcoming drug delivery challenges for potent anticancer agents.
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