title: Innovative drug delivery nanosystems improve the anti-tumor activity in vitro and in vivo of anti-estrogens in human breast cancer and multiple myeloma.
abstract: Anticancer drug efficiency is governed by its bioavailability. In order to increase this parameter, we synthesized several injectable and biodegradable systems based on incorporation of anti-estrogens (AEs) in nanoparticles (NPs) and liposomes were synthesized. Both nanospheres (NS) and nanocapsules (NCs, polymers with an oily core in which AEs were solubilized) incorporated high amounts of 4-hydroxy-tamoxifen (4-HT) or RU 58668 (RU). Physico-chemical and biological parameters of these delivery systems, and coupling of polyethylene-glycol chains on the NP surface revealed to enhance the anti-tumoral activity of trapped AEs in a breast cancer MCF-7 cell xenograft model and to induce apoptosis. These features correlated with an augmentation of p21(Waf-1/Cip1) and of p27(Kip1) and a concomitant decrease of cyclin D1 and E in tumor extracts. Liposomes containing various ratios of lipids enhanced the apoptotic activity of RU in several multiple myeloma (MM) cell lines tested by flow cytometry. MM cell lines expressed both estrogen receptor alpha and beta subtypes except Karpas 620. Karpas 620 cells which did not respond to AEs became responsive following ER cDNA transfection. A new MM xenograft model was generated after s.c. injection of RPMI 8226 cells in nude mice. RU-loaded liposomes, administered i.v. in this model, at a dose of 12mgRU/kg/week, induced the arrest of tumor growth contrary to free RU or to empty liposomes. Thus, the drug delivery of anti-estrogens enhances their ability to arrest the growth of tumors which express estrogen receptors and are of particular interest for estrogen-dependent breast cancer treatment. In addition it represents a new potent therapeutic approach for multiple myeloma.
authors.affiliation: UMR CNRS 8612, Pharmacologie Cellulaire et Moléculaire des anticancéreux, 5 rue Jean-Baptiste Clément, 92296 Châtenay-Malabry Cedex, France.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Maillard
authors.forename: Thibault
authors.initials: T
authors.lastname: Ameller
authors.forename: Juliette
authors.initials: J
authors.lastname: Gauduchon
authors.forename: Angélique
authors.initials: A
authors.lastname: Gougelet
authors.forename: Fabrice
authors.initials: F
authors.lastname: Gouilleux
authors.forename: Philippe
authors.initials: P
authors.lastname: Legrand
authors.forename: Véronique
authors.initials: V
authors.lastname: Marsaud
authors.forename: Elias
authors.initials: E
authors.lastname: Fattal
authors.forename: Brigitte
authors.initials: B
authors.lastname: Sola
authors.forename: Jack-Michel
authors.initials: JM
authors.lastname: Renoir
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms; D002214:Capsules; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D004337:Drug Carriers; D020847:Estrogen Receptor Modulators / Q000008:administration & dosage / Q000494:pharmacology*; D005260:Female; D006801:Humans; D008081:Liposomes; D009101:Multiple Myeloma / Q000473:pathology; D013629:Tamoxifen / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000633:toxicity*; D014162:Transfection
chemical_list: D002214:Capsules; D004337:Drug Carriers; D020847:Estrogen Receptor Modulators; D008081:Liposomes; D013629:Tamoxifen; C016601:afimoxifene