Nanomedicine: Nanotechnology, Biology and Medicine
Volume 4, Issue 2 , Pages 155-166 , June 2008

Liposomal delivery improves the growth-inhibitory and apoptotic activity of low doses of gemcitabine in multiple myeloma cancer cells

  • Christian Celia, PhD

      Affiliations

    • Department of Pharmacobiological Sciences, Faculty of Pharmacy, University “Magna Græcia” of Catanzaro, Campus Universitario – Building of BioSciences, Viale Europa, I-88100 Germaneto (CZ), Italy
    • ,
  • Natalia Malara, MD, PhD

      Affiliations

    • Department of Experimental and Clinical Medicine, Faculty of Medicine, University “Magna Græcia” of Catanzaro, Campus Universitario – Building of BioSciences, Viale Europa, I-88100 Germaneto (CZ), Italy
    • ,
  • Rosa Terracciano, PhD

      Affiliations

    • Department of Experimental and Clinical Medicine, Faculty of Medicine, University “Magna Græcia” of Catanzaro, Campus Universitario – Building of BioSciences, Viale Europa, I-88100 Germaneto (CZ), Italy
    • ,
  • Donato Cosco, PhD

      Affiliations

    • Department of Pharmacobiological Sciences, Faculty of Pharmacy, University “Magna Græcia” of Catanzaro, Campus Universitario – Building of BioSciences, Viale Europa, I-88100 Germaneto (CZ), Italy
    • ,
  • Donatella Paolino, PhD

      Affiliations

    • Department of Experimental and Clinical Medicine, Faculty of Medicine, University “Magna Græcia” of Catanzaro, Campus Universitario – Building of BioSciences, Viale Europa, I-88100 Germaneto (CZ), Italy
    • ,
  • Massimo Fresta, PhD

      Affiliations

    • Department of Pharmacobiological Sciences, Faculty of Pharmacy, University “Magna Græcia” of Catanzaro, Campus Universitario – Building of BioSciences, Viale Europa, I-88100 Germaneto (CZ), Italy
    • Corresponding Author InformationCorresponding author. Department of Pharmacobiological Sciences, Faculty of Pharmacy, University “Magna Græcia" of Catanzaro, Campus Universitario – Building of BioSciences, Viale Europa, I-88100 Germaneto (CZ), Italy.
    • ,
  • Rocco Savino, PhD

      Affiliations

    • Department of Experimental and Clinical Medicine, Faculty of Medicine, University “Magna Græcia” of Catanzaro, Campus Universitario – Building of BioSciences, Viale Europa, I-88100 Germaneto (CZ), Italy

Received 24 August 2007 ,Accepted 18 February 2008.

References 

  1. Sirohi B, Powles R. Multiple myeloma. Lancet. 2004;363:875–887
  2. Hideshima T, Anderson KC. Molecular mechanisms of novel therapeutic approaches for multiple myeloma. Nat Rev Cancer. 2002;2:927–937
  3. Hallek M, Bergsagel PL, Anderson KC. Multiple myeloma: increasing evidence for a multistep transformation process. Blood. 1998;91:3–21
  4. Anderson KC. Targeted therapy for multiple myeloma. Semin Hematol. 2001;38:286–294
  5. Klein B, Zhang XG, Content J, Houssian F, Aarden L, Piechaczyk M, et al. Paracrine rather than autocrine regulation of multiple myeloma—cell growth and differentiation by interleukin-6. Blood. 1989;73:517–526
  6. Klein B, Zhang XG, Bataille R. Interleukin-6 in human multiple myeloma. Blood. 1995;85:863–872
  7. Lichtenstein A, Tu Y, Fady C, Vescio R, Berenson J. Interleukin-6 inhibits apoptosis of malignant plasma cells. Cell Immunol. 1995;162:248–255
  8. Maillard S, Ameller T, Gauduchon J, Gougelet A, Gouilleux F, Legrand P, et al. Innovative drug delivery nanosystems improve anti-tumor activity in vitro and in vivo of anti-estrogens in human breast cancer and multiple myeloma. J Steroid Biochem Mol Biol. 2005;94:111–121
  9. Alexanian R, Yap BS, Bodey GP. Prednisone pulse therapy for refractory myeloma. Blood. 1983;62:572–577
  10. Alexanian R, Dimopoulos MA, Delasalle K, Barlogie B. Primary dexamethasone treatment of multiple myeloma. Blood. 1992;80:887–890
  11. Grigorieva I, Thomas H, Epstein J. The bone marrow stromal environment is major factor in myeloma cell resistance to dexamethasone. Exp Hematol. 1998;26:597–603
  12. Noble S, Goa KL. Gemcitabine. A review of its pharmacology and clinical potential in non-small cell lung cancer and pancreatic cancer. Drugs. 1997;54:447–472
  13. Leleu X, Troncy J, Bouafia F, Michallet M, Facon T, Dumontet C. Evaluation of gemcitabine in relapsed or refractory multiple myeloma. Haematologica. 2004;89:ELT15
  14. Nabhan C, Gajria D, Krett NL, Gandhi V, Ghias K, Rosen ST. Caspase activation is required for gemcitabine activity in multiple myeloma cell lines. Mol Cancer Ther. 2002;1:1221–1227
  15. Offidani M, Mele A, Corvetta L, Marconi M, Malerba L, Olivieri A, et al. Gemcitabine alone or combined with cisplatin in relapsed or refractory multiple myeloma. Leuk Lymphoma. 2002;43:1273–1279
  16. Barlesi F, Villani P, Doddoli C, Gimenez C, Kleisbauer JP. Gemcitabine induced severe pulmonary toxicity. Fundam Clin Pharmacol. 2004;18:85–91
  17. Kouroussis C, Mavroudis D, Kakolyris S, Voloudaki A, Kalbakis K, Souglakos J, et al. High incidence of pulmonary toxicity of weekly docetaxel and gemcitabine in patients with nonsmall cell lung cancer: results of a dose-finding study. Lung Cancer. 2004;44:363–368
  18. Santini D, Tonini G, Abbate A, Di Cosimo S, Gravante G, Vincenzi B, et al. Gemcitabine-induced atrial fibrillation: a hitherto unreported manifestation of drug toxicity. Ann Oncol. 2000;11:479–481
  19. Celano M, Calvagno MG, Bulotta S, Paolino D, Arturi F, Rotiroti D, et al. Cytotoxic effects of gemcitabine-loaded liposomes in human anaplastic thyroid carcinoma cells. BMC Cancer. 2004;4:63–68
  20. Celia C, Calvagno MG, Paolino D, Bulotta S, Ventura CA, Russo D, et al. Improved in vitro anti-tumoral activity, intracellular uptake and apoptotic induction of gemcitabine-loaded pegylated unilamellar liposomes. J Nanosci Nanotechnol. 2008;8:2102–2103
  21. Offidani M, Corvatta L, Marconi M, Visani G, Alesiani F, Brunori M, et al. Low-dose thalidomide with pegylated liposomal doxorubicin and high-dose dexamethasone for relapsed/refractory multiple myeloma: a prospective, multicenter, phase II study. Haematologica. 2006;91:133–136
  22. Offidani M, Corvatta L, Piersantelli MN, Visani G, Alesiani F, Brunori M, et al. Thalidomide, dexamethasone, and pegylated liposomal doxorubicin (ThaDD) for patients older than 65 years with newly diagnosed multiple myeloma. Blood. 2006;108:2159–2164
  23. Boulikas T. Low toxicity and anticancer activity of a novel liposomal cisplatin (Lipoplatin) in mouse xenografts. Oncol Rep. 2004;12:3–12
  24. Dvorak J, Zoul Z, Melichar B, Petera J, Vesely P, Vosmik M, et al. Liposomal doxorubicin combined with regional hyperthermia: reducing systemic toxicity and improving locoregional efficacy in the treatment of solid tumors. J Chemother. 2004;5:34–36
  25. Li X, Ruan GR, Lu WL, Hong HY, Liang GW, Zhang YT, et al. A novel stealth liposomal topotecan with amlodipine: apoptotic effect is associated with deletion of intracellular Ca2+ by amlodipine thus leading to an enhanced antitumor activity in leukemia. J Control Rel. 2006;112:186–198
  26. Gabizon A, Papahadjopoulos D. Liposome formulations with prolonged circulation time in blood and enhanced uptake by tumors. Proc Natl Acad Sci U S A. 1988;85:6949–6953
  27. Drummond DC, Meyer O, Hong K, Kirpotin DB, Papahadjopoulos D. Optimizing liposomes for delivery of chemotherapeutic agents to solid tumors. Pharmacol Rev. 1999;51:691–743
  28. Furneri PM, Fresta M, Puglisi G, Tempera G. Ofloxacin-loaded liposomes: in vitro activity and drug accumulation in bacteria. Antimicrob Agents Chemother. 2000;44:2458–2464
  29. Hyvonen Z, Ronkko S, Toppinen MR, Jaaskelainen I, Plotniece A, Urtti A. Dioleoyl phosphatidylethanolamine and PEG-lipid conjugates modify DNA delivery mediated by 1,4-dihydropyridine amphiphiles. J Control Rel. 2004;99:177–190
  30. Xiong XB, Huang Y, Lu WL, Zhang H, Zhang X, Zhang Q. Enhanced intracellular uptake of sterically stabilized liposomal doxorubicin in vitro resulting in improved antitumor activity in vivo. Pharm Res. 2005;22:933–939
  31. Gabizon AA, Shmeeda H, Zalipsky S. Pros and cons of the liposome platform in cancer drug targeting. J Liposome Res. 2006;16:175–183
  32. Nakajima N, Ikada Y. Fusogenic activity of various water-soluble polymers. J Biomater Sci Polym Ed. 1994;6:751–759
  33. Simoes S, Slepushkin V, Duzgunes N, Pedroso de Lima MC. On the mechanisms of internalization and intracellular delivery mediated by pH-sensitive liposomes. Biochim Biophys Acta. 2001;1515:23–37
  34. Knutton S. Studies of membrane fusion. III. Fusion of erythrocytes with polyethylene glycol. J Cell Sci. 1979;36:61–72
  35. Calvagno MG, Celia C, Paolino D, Cosco D, Iannone M, Castelli F, et al. Effects of lipid composition and preparation conditions on physical-chemical properties, technological parameters and in vitro biological activity of gemcitabine-loaded liposomes. Curr Drug Deliv. 2007;4:89–101
  36. Chiu GN, Abraham SA, Ickenstein LM, Ng R, Karlsson G, Edwards K, et al. Encapsulation of doxorubicin into thermosensitive liposomes via complexation with the transition metal manganese. J Control Rel. 2005;104:271–288
  37. Pavelic Z, Skalko-Basnet N, Filipovic-Grcic J, Martinac A, Jalsenjak I. Development and in vitro evaluation of a liposomal vaginal delivery system for acyclovir. J Control Rel. 2005;106:34–43
  38. Tassone P, Neri P, Burger R, Savino R, Shammas M, Catley L, et al. Combination therapy with IL-6 receptor super-antagonist Sant7 and dexamethasone induces antitumor effects in a novel SCID-hu in vivo model of human multiple myeloma. Clinical Cancer Res. 2005;11:2451–2458
  39. Arcone R, Pucci P, Zappacosta F, Fontaine V, Malorni A, Marino G, et al. Single-step purification and structural characterization of human interleukin-6 produced in Escherichia coli from a T7 RNA polymerase expression vector. Eur J Biochem. 1991;198:541–547
  40. Eudey TL. Statistical considerations in DNA flow cytometry. Stat Sci. 1996;11:320–334
  41. Shreeram S, Sparks A, Lane DP, Blow JJ. Cell type-specific responses of human cells to inhibition of replication licensing. Oncogene. 2002;21:6624–6632
  42. Krett NL, Ayres M, Nabhan C, Ma C, Nowak B, Nawrocki S, et al. In vitro assessment of nucleoside analogs in multiple myeloma. Cancer Chemother Pharmacol. 2004;54:113–121
  43. Hedley DW, Shankey TV, Wheeless LL. DNA cytometry consensus conference. Cytometry. 1993;14:471–500
  44. Hunter DG, Frisken BJ. Effect of extrusion pressure and lipid properties on the size and polydispersity of lipid vesicles. J. Biophys. 1998;74:2996–3002
  45. Fresta M, Ricci M, Rossi C, Furneri PM, Puglisi G. Antimicrobial nonapeptide leucinostatin α-dependent effects on the physical properties of phospholipid model membranes. J Colloid Interface Sci. 2000;226:222–230
  46. Ahsan F, Rivas IP, Khan MA, Torres Suarez AI. Targeting to macrophages: role of physicochemical properties of particulate carriers—liposomes and microspheres—on the phagocytosis by macrophages. J Control Rel. 2002;79:29–40
  47. Kneuer C, Ehrhardt C, Bakowsky H, Kumar MN, Oberle V, Lehr CM, et al. The influence of physicochemical parameters on the efficacy of non-viral DNA transfection complexes: a comparative study. J Nanosci Nanotechnol. 2006;6:2776–2782
  48. Cullis PR, Hope MJ, Bally MB, Madden TD, Mayer LD, Fenske DB. Influence of pH gradient on the transbilayer transport of drugs, lipids, peptides and metal ions into large unilamellar vesicles. Biochim Biophys Acta. 1997;1331:187–211
  49. Abraham SA, Edwards K, Karlsson G, Hudon N, Mayer LD, Bally MB. An evaluation of transmembrane ion gradient-mediated encapsulation of topotecan within liposomes. J Control Rel. 2004;96:449–461
  50. Fritze A, Hens F, Kimpfler A, Schubert R, Peschka-Suss R. Remote loading of doxorubicin into liposomes driven by a transmembrane phosphate gradient. Biochim Biophys Acta. 2006;1758:1633–1640
  51. Tassone P, Galea E, Forciniti S, Tagliaferri P, Venuta S. The IL-6 receptor super-antagonist Sant-7 enhances antiproliferative and apoptotic effects induced by dexamethasone and zoledronic acid on multiple myeloma cells. Int J Oncol. 2002;21:867–873
  52. Juge-Morineau N, Harousseau JL, Amiot M, Bataille R. The retinoblastoma susceptibility gene RB-1 in multiple myeloma. Leuk Lymphoma. 1997;24:229–237
  53. Gazitt Y, Rothenberg ML, Hilsenbeck SG, Fey V, Thomas C, Montegomrey W. Bcl-2 overexpression is associated with resistance to paclitaxel, but not gemcitabine, in multiple myeloma cells. Int J Oncol. 1998;13:839–848
  54. Gazitt Y, Shaughnessy P, Rothenberg ML. A phase II trial with gemcitabine and paclitaxel for the treatment of refractory and relapsed multiple myeloma patients. Oncol Rep. 2006;16:877–884
  55. Paolino D, Iannone M, Cardile V, Renis M, Puglisi G, Rotiroti D, et al. Tolerability and improved protective action of idebenone-loaded pegylated liposomes on ethanol-induced injury in primary cortical astrocytes. J Pharm Sci. 2004;93:1815–1827
  56. Fattal E, Couvreur P, Dubernet C. “Smart" delivery of antisense oligonucleotides by anionic pH-sensitive liposomes. Adv Drug Deliv Rev. 2004;56:931–946
  57. Koynova R, MacDonald RC. Lipid transfer between cationic vesicles and lipid-DNA lipoplexes: effect of serum. Biochim Biophys Acta. 2005;1714:63–70
  58. Maillard S, Gauduchon J, Marsaud V, Gouilleux F, Connault E, Opolon P, et al. Improved antitumoral properties of pure antiestrogen RU 58668-loaded liposomes in multiple myeloma. J Steroid Biochem Mol Biol. 2006;100:67–78
  59. Dan N. Effect of liposome charge and PEG polymer layer thickness on cell-liposome electrostatic interactions. Biochim Biophys Acta. 2002;1564:343–348
  60. Borowik T, Widerak K, Ugorski M, Langner M. Combined effect of surface electrostatic charge and poly(ethylglycol) on the association of liposomes with colon carcinoma cells. J Lipid Res. 2005;15:199–213

 This paper was financially supported by an AIRC 2005 grant, MIUR grants (PRIN 2005 and PRIN 2006), and a Ministero della Salute – Regione Calabria (Dipartimento Tutela della Salute Politiche Sanitarie e Sociali) grant. Dr. Natalia Malara was supported by a FIRC fellowship.

PII: S1549-9634(08)00033-6

doi: 10.1016/j.nano.2008.02.003

Nanomedicine: Nanotechnology, Biology and Medicine
Volume 4, Issue 2 , Pages 155-166 , June 2008

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