Pharmaceutical Research

, Volume 27, Issue 2, pp 327–339 | Cite as

Therapeutic Potential of New 4-hydroxy-tamoxifen-Loaded pH-gradient Liposomes in a Multiple Myeloma Experimental Model

  • Giorgia Urbinati
  • Davide Audisio
  • Véronique Marsaud
  • Vincent Plassat
  • Silvia Arpicco
  • Brigitte Sola
  • Elias Fattal
  • Jack-Michel Renoir
Research Paper



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.


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.


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.


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.


breast cancer hydroxy-tamoxifen multiple myeloma pH-gradient Stealth® liposomes 









1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(Polyethyleneglycol)-2000] (ammonium salt)






estrogen receptor





We thank Besins Iscovesco for the generous gift of 4HT, J. Bignon for FACS analyses and M. Pons and P. Ballaguer for the gift of MELN cells. This work was supported by the Ligue Nationale contre le Cancer through a fellowship offered to G.U. and financial support was provided to J-M. R from the Comités du Cher, de l’Indre et des Hauts de Seine of the Ligue Nationale contre le Cancer.


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Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • Giorgia Urbinati
    • 1
    • 2
    • 3
  • Davide Audisio
    • 2
    • 3
    • 4
  • Véronique Marsaud
    • 1
    • 2
    • 3
  • Vincent Plassat
    • 1
    • 2
    • 3
  • Silvia Arpicco
    • 5
  • Brigitte Sola
    • 6
  • Elias Fattal
    • 1
    • 2
    • 3
    • 7
  • Jack-Michel Renoir
    • 1
    • 2
    • 3
  1. 1.CNRS, UMR 8612, Physico-Chimie, Pharmacotechnie, Biopharmacie, Laboratoire Pharmacologie Cellulaire et Moléculaire des Anticancéreux, Faculté de PharmacieChâtenay-MalabryFrance
  2. 2.University Paris-SudOrsayFrance
  3. 3.IFR 141Châtenay-MalabryFrance
  4. 4.CNRS, BIOCIS-UMR 8076Laboratoire de Chimie ThérapeutiqueChâtenay-MalabryFrance
  5. 5.Facoltà di FarmaciaUniversità degli studi di TorinoTorinoItaly
  6. 6.Biologie Moléculaire et Cellulaire de la Signalisation, EA 3919, IFR186Université de Caen Basse NormandieCaenFrance
  7. 7.CNRS, UMR 8612Laboratoire de Vectorisation Pharmaceutique de Molécules fragilesChâtenay-MalabryFrance

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