Liposomes loaded with histone deacetylase inhibitors for breast cancer therapy.
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.
Urbinati
Giorgia
G
Centre National de la Recherche Scientifique, UMR 8612, Faculté de Pharmacie, 5 rue J.B. Clément, Châtenay-Malabry, F-92296, France.
Marsaud
Véronique
V
Plassat
Vincent
V
Fattal
Elias
E
Lesieur
Sylviane
S
Renoir
Jack-Michel
JM
D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D055598:Chemical Phenomena; D004337:Drug Carriers; D016503:Drug Delivery Systems; D004355:Drug Stability; D004958:Estradiol / Q000378:metabolism; D047628:Estrogen Receptor alpha / Q000378:metabolism; D005260:Female; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008081:Liposomes; D010316:Particle Size; D013449:Sulfonamides
C531199:7-phenyl-2,4,6-heptatrienoylhydroxamic acid; D000970:Antineoplastic Agents; D004337:Drug Carriers; D047628:Estrogen Receptor alpha; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D008081:Liposomes; D013449:Sulfonamides; C012589:trichostatin A; D004958:Estradiol; C487081:belinostat