title: Therapeutic potential of new 4-hydroxy-tamoxifen-loaded pH-gradient liposomes in a multiple myeloma experimental model.
abstract: OBJECTIVE
  To determine the better liposomal formulation incorporating the active metabolite of tamoxifen, 4-hydroxy-tamoxifen (4HT) and the biological impact of 4HT-pH-gradient liposomes on response to in vivo treatment.
  
  
  METHODS
  Several pegylated liposomes were formulated by varying the composition of lipids, increasing external pH from 7.4 to 9.0 and doubling the lipid concentration. Dipalmitoylphosphatidylcholine / cholesterol / distearoylphosphoethanolamine poly(ethylene)glycol liposomes (DL-9 liposomes) were chosen for their physico-chemical properties. Toxicity and release kinetics were assessed in breast cancer MCF-7 as well as in multiple myeloma (MM) cells. In vivo antitumor activity and bio-distribution were measured in the RPMI8226 MM model.
  
  
  RESULTS
  Compared to conventional non-pH-gradient liposomes, 4HT-DL-9 liposomes resulted in concentration of up to 1 mM 4HT, greater stability, relative toxicity and slow 4HT release. Intravenous injections of 4HT-DL-9 liposomes at 4 mg/kg/week blocked MM tumor growth. Ki67 and CD34 labeling decreased in treated tumors, concomitantly with increase of activated caspase-3 supporting a cell proliferation arrest, a decrease of tumor vasculature and the induction of tumor cell death.
  
  
  CONCLUSIONS
  This antitumor effect was assumed to be the result of a modified biodistribution of 4HT once trapped in DL-9 liposomes. Such 4HT-containing pH-gradient Stealth nanocarriers could be helpful for MM treatment.
authors.affiliation: CNRS, UMR 8612, Physico-Chimie, Pharmacotechnie, Biopharmacie, Laboratoire Pharmacologie Cellulaire et Moléculaire des Anticancéreux, Faculté de Pharmacie, 5 rue J.B. Clément, Châtenay-Malabry, F-92296, France.
authors.forename: Giorgia
authors.initials: G
authors.lastname: Urbinati
authors.forename: Davide
authors.initials: D
authors.lastname: Audisio
authors.forename: Véronique
authors.initials: V
authors.lastname: Marsaud
authors.forename: Vincent
authors.initials: V
authors.lastname: Plassat
authors.forename: Silvia
authors.initials: S
authors.lastname: Arpicco
authors.forename: Brigitte
authors.initials: B
authors.lastname: Sola
authors.forename: Elias
authors.initials: E
authors.lastname: Fattal
authors.forename: Jack-Michel
authors.initials: JM
authors.lastname: Renoir
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008081:Liposomes; D051379:Mice; D008819:Mice, Nude; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D018892:Proton-Motive Force / Q000187:drug effects* / Q000502:physiology; D013629:Tamoxifen / Q000008:administration & dosage / Q000031:analogs & derivatives*; D023041:Xenograft Model Antitumor Assays / Q000379:methods
chemical_list: D008081:Liposomes; D013629:Tamoxifen; C016601:afimoxifene