Skip to main content
SpringerLink
Log in

Liposome Formulations of Hydrophobic Drugs

  • Protocol
  • First Online:
Liposomes

Part of the book series: Methods in Molecular Biology ((MIMB,volume 1522))

Abstract

Here we report methods of preparation for liposome formulations containing lipophilic drugs. In contrast to the encapsulation of water soluble compounds into the entrapped aqueous volume of a liposome, drugs with lipophilic properties are incorporated into the phospholipid bilayer membrane. Water-soluble molecules, for example cytotoxic or antiviral nucleosides can be transformed into lipophilic compounds by attachment of long alkyl chains, allowing their stable incorporation into liposome membranes and taking advantage of the high loading capacity lipid bilayers provide for lipophilic molecules. We created a new class of cytotoxic drugs by chemical transformation of the hydrophilic drugs cytosine-arabinoside (ara-C), 5-fluoro-deoxyuridine (5-FdU), and ethinylcytidine (ETC) into lipophilic compounds and their formulation in liposomes.

The concept of chemical modification of water-soluble molecules by attachment of long alkyl chains and their stable incorporation into liposome bilayer membranes represent a very promising method for the development of new drugs not only for the treatment of tumors or infections but also for many other diseases.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Protocol
USD 49.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 89.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 119.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Hofheinz RD, Gnad-Vogt SU, Beyer U, Hochhaus A (2005) Liposomal encapsulated anti-cancer drugs. Anticancer Drugs 16:691–707

    Article  CAS  PubMed  Google Scholar 

  2. Perez-Lopez ME, Curiel T, Gomez JG, Jorge M (2007) Role of pegylated liposomal doxorubicin (Caelyx) in the treatment of relapsing ovarian cancer. Anticancer Drugs 18:611–617

    Article  CAS  PubMed  Google Scholar 

  3. Porter CA, Rifkin RM (2007) Clinical benefits and economic analysis of pegylated liposomal doxorubicin/vincristine/dexamethasone versus doxorubicin/vincristine/dexamethasone in patients with newly diagnosed multiple myeloma. Clin Lymphoma Myeloma S4:S150–S155

    Article  Google Scholar 

  4. Thomas DA, Sarris AH, Cortes J, Faderl S, O'Brien S, Giles FJ, Garcia-Manero G, Rodriguez MA, Cabanillas F, Kantarjian H (2006) Phase II study of sphingosomal vincristine in patients with recurrent or refractory adult acute lymphocytic leukemia. Cancer 106:120–127

    Article  CAS  PubMed  Google Scholar 

  5. Hennenfent KL, Govindan R (2006) Novel formulations of taxanes: a review. Old wine in a new bottle? Ann Oncol 17:735–749

    Article  CAS  PubMed  Google Scholar 

  6. Strickley RG (2004) Solubilizing excipients in oral and injectable formulations. Pharm Res 21:201–230

    Article  CAS  PubMed  Google Scholar 

  7. Fahr A, Liu X (2007) Drug delivery strategies for poorly water-soluble drugs. Expert Opin Drug Deliv 4:403–416

    Article  CAS  PubMed  Google Scholar 

  8. ten Tije AJ, Verweij J, Loos WJ, Sparreboom A (2003) Pharmacological effects of formulation vehicles: implications for cancer chemotherapy. Clin Pharmacokinet 42:665–685

    Article  PubMed  Google Scholar 

  9. Brusa P, Immordino ML, Rocco F, Cattel L (2007) Antitumor activity and pharmacokinetics of liposomes containing lipophilic gemcitabine prodrugs. Anticancer Res 27:195–199

    CAS  PubMed  Google Scholar 

  10. Bergman AM, Kuiper CM, Noordhuis P, Smid K, Voorn DA, Comijn EM, Myhren F, Sandvold ML, Hendriks HR, Fodstad O, Breistol K, Peters GJ (2004) Antiproliferative activity and mechanism of action of fatty acid derivatives of gemcitabine in leukemia and solid tumor cell lines and in human xenografts. Nucleosides Nucleotides Nucleic Acids 23:1329–1333

    Article  CAS  PubMed  Google Scholar 

  11. Stevens PJ, Sekido M, Lee RJ (2004) A folate receptor-targeted lipid nanoparticle formulation for a lipophilic paclitaxel prodrug. Pharm Res 21:2153–2157

    Article  CAS  PubMed  Google Scholar 

  12. Pignatello R, Puleo A, Puglisi G, Vicari L, Messina A (2003) Effect of liposomal delivery on in vitro antitumor activity of lipophilic conjugates of methotrexate with lipoamino acids. Drug Deliv 10:95–100

    Article  CAS  PubMed  Google Scholar 

  13. Zerouga M, Stillwell W, Jenski LJ (2002) Synthesis of a novel phosphatidylcholine conjugated to docosahexaenoic acid and methotrexate that inhibits cell proliferation. Anticancer Drugs 13:301–311

    Article  CAS  PubMed  Google Scholar 

  14. Harrington KJ, Syrigos KN, Uster PS, Zetter A, Lewanski CR, Gullick WJ, Vile RG, Stewart JS (2004) Targeted radiosensitisation by pegylated liposome-encapsulated 3′, 5′-O-dipalmitoyl 5-iodo-2′-deoxyuridine in a head and neck cancer xenograft model. Br J Cancer 91:366–373

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Hamada A, Kawaguchi T, Nakano M (2002) Clinical pharmacokinetics of cytarabine formulations. Clin Pharmacokinet 41:705–718

    Article  CAS  PubMed  Google Scholar 

  16. Rubas W, Supersaxo A, Weder HG, Hartmann HR, Hengartner H, Schott H, Schwendener RA (1986) Treatment of murine L1210 leukemia and melanoma B16 with lipophilic cytosine arabinoside prodrugs incorporated into unilamellar liposomes. Int J Cancer 37:149–154

    Article  CAS  PubMed  Google Scholar 

  17. Schwendener RA, Schott H (1992) Treatment of L1210 murine leukemia with liposome - incorporated N4-hexadecyl-1-β-d-arabino-furanosyl-cytosine. Int J Cancer 51:466–469

    Article  CAS  PubMed  Google Scholar 

  18. Schwendener RA, Schott H (2005) Lipophilic arabinofuranosyl cytosine derivatives in liposomes. Meth Enzymol 391:58–70

    Article  CAS  PubMed  Google Scholar 

  19. Horber DH, Schott H, Schwendener RA (1995) Cellular pharmacology of a liposomal preparation of N4-hexadecyl-1-β-d-arabino-furanosylcytosine, a lipophilic derivative of 1-β-d-arabinofuranosylcytosine. Br J Cancer 71:957–962

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Horber DH, von Ballmoos P, Schott H, Schwendener RA (1995) Cell cycle dependent cytotoxicity and induction of apoptosis by N4-hexadecyl-1-β-d-arabinofuranosylcytosine, a new lipophilic derivative of 1-β-d-arabino-furanosylcytosine. Br J Cancer 72:1067–1073

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Horber DH, Schott H, Schwendener RA (1995) Cellular pharmacology of N4-hexadecyl-1-β-d-arabinofuranosylcytosine (NHAC) in the human leukemic cell lines K-562 and U-937. Cancer Chemother Pharmacol 36:483–492

    Article  CAS  PubMed  Google Scholar 

  22. Schwendener RA, Friedl K, Depenbrock H, Schott H, Hanauske AR (2001) In vitro activity of liposomal N4octadecyl-1-β-d-arabino-furanosylcytosine (NOAC), a new lipophilic derivative of 1-β-d-arabino-furanocylcytosine on biopsized clonogenic human tumor cells and hematopoietic precursor cells. Invest New Drugs 19:203–210

    Article  CAS  PubMed  Google Scholar 

  23. Wasan KM, Brocks DR, Lee SD, Sachs-Barrable K, Thornton SJ (2008) Impact of lipoproteins on the biological activity and disposition of hydrophobic drugs: implications for drug discovery. Nat Rev Drug Discov 7:84–99

    Article  CAS  PubMed  Google Scholar 

  24. Rensen PC, de Vrueh RL, Kuiper J, Bijsterbosch MK, Biessen EA, van Berkel TJ (2001) Recombinant lipoproteins: lipoprotein-like lipid particles for drug targeting. Adv Drug Deliv Rev 47:251–276

    Article  CAS  PubMed  Google Scholar 

  25. Koller-Lucae SKM, Schott H, Schwendener RA (1997) Pharmacokinetic properties in mice and interactions with human blood in vitro of liposomal N4-octadecyl-1-β-d-arabinofuranosylcytosine (NOAC), a new anticancer drug. J Pharmacol Exp Thera 282:1572–1580

    CAS  Google Scholar 

  26. Koller-Lucae SKM, Suter MJ, Rentsch KM, Schott H, Schwendener RA (1999) Metabolism of the new liposomal anticancer drug N4-octadecyl-1-β-d-arabinofuranosylcytosine (NOAC) in mice. Drug Metab Dispos 27:342–350

    CAS  PubMed  Google Scholar 

  27. Koller-Lucae SM, Schott H, Schwendener RA (1999) Low density lipoprotein and liposome mediated uptake and cytotoxic effect of N4-octadecyl-1-β-d-arabinofuranosylcytosine (NOAC) in Daudi lymphoma cells. Br J Cancer 80:1542–1549

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Horber DH, Cattaneo-Pangrazzi RM, von Ballmoos P, Schott H, Ludwig PS, Eriksson S, Fichtner I, Schwendener RA (2000) Cytotoxicity, cell cycle perturbations and apoptosis in human tumor cells by lipophilic N4-alkyl-1-β-d-arabinofuranosylcytosine derivatives and the new heteronucleoside phosphate dimer arabinocytidylyl-(5′ → 5′)-N4-octadecyl-1-β-d-ara-C. J Cancer Res Clin Oncol 126:311–319

    Article  CAS  PubMed  Google Scholar 

  29. Cattaneo-Pangrazzi RM, Schott H, Wunderli-Allenspach H, Derighetti M, Schwendener RA (2000) Induction of cell cycle-dependent cytotoxicity and apoptosis by new heterodinucleoside phosphate dimers of 5-fluorodeoxyuridine in PC-3 human prostate cancer cells. Biochem Pharmacol 60:1887–1896

    Article  CAS  PubMed  Google Scholar 

  30. Cattaneo-Pangrazzi RM, Schott H, Schwendener RA (2000) The novel heterodinucleoside dimer 5-FdU-NOAC is a potent cytotoxic drug and a p53-independent inducer of apoptosis in the androgen-independent human prostate cancer cell lines PC-3 and DU-145. Prostate 45:8–18

    Article  CAS  PubMed  Google Scholar 

  31. Marty C, Ballmer-Hofer K, Neri D, Klemenz R, Schott H, Schwendener RA (2002) Cytotoxic targeting of F9 teratocarcinoma tumours with anti-ED-B fibronectin scFv antibody modified liposomes. Br J Cancer 87:106–112

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Takatori S, Kanda H, Takenaka K, Wataya Y, Matsuda A, Fukushima M, Shimamoto Y, Tanaka M, Sasaki T (1999) Antitumor mechanisms and metabolism of the novel antitumor nucleoside analogues, 1-(3-C-ethynyl-β-d-ribo-pentofuranosyl)cytosine and 1-(3-C-ethynyl-β-d-ribo-pentofuranosyl)uracil. Cancer Chemother Pharmacol 44:97–104

    Article  CAS  PubMed  Google Scholar 

  33. Schwendener RA, Gowland P, Horber DH, Zahner R, Schertler A, Schott H (1994) New lipophilic acyl/alkyl dinucleoside phosphates as derivatives of 3′-azido-3′-deoxythymidine: inhibition of HIV-1 replication in vitro and antiviral activity against Rauscher leukemia virus infected mice with delayed treatment regimens. Antiviral Res 24:79–93

    Article  CAS  PubMed  Google Scholar 

  34. Peghini PA, Zahner R, Kuster H, Schott H, Schwendener RA (1998) In vitro inhibition of hepatitis B virus replication and pharmacokinetic properties of new lipophilic dinucleoside phosphate derivatives. Antivir Chem Chemother 9:117–126

    Article  CAS  PubMed  Google Scholar 

  35. Mayer LD, Hope MJ, Cullis PR (1986) Vesicles of variable sizes produced by a rapid extrusion procedure. Biochim Biophys Acta 858:161–168

    Article  CAS  PubMed  Google Scholar 

  36. Rentsch KM, Schwendener RA, Schott H, Hänseler E (1997) Pharmacokinetics of N4-octadecyl-1-β-d-arabinofuranosylcytosine (NOAC) in plasma and whole blood after intravenous and oral application in mice. J Pharm Pharmacol 49:1076–1081

    Article  CAS  PubMed  Google Scholar 

  37. Schwendener RA, Asanger M, Weder HG (1981) The preparation of large bilayer liposomes: controlled removal of n-alkyl-glucoside detergents from lipid/detergent micelles. Biochem Biophys Res Commun 100:1055–1062

    Article  CAS  PubMed  Google Scholar 

  38. Schwendener RA (1986) The preparation of large volumes of homogeneous, sterile liposomes containing various lipophilic cytostatic drugs by the use of a capillary dialyzer. Cancer Drug Deliv 3:123–129

    Article  CAS  PubMed  Google Scholar 

  39. Allen TM (1994) Long-circulating (sterically stabilized) liposomes for targeted drug delivery. Trends Pharmacol Sci 15:215–220

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Laboratory of Liposome Research, Institute of Molecular Cancer Research, University of Zürich, Winterthurerstrasse 190, 8057, Zurich, Switzerland

    Reto A. Schwendener

  2. Institute of Organic Chemistry, Eberhard-Karls University, Auf der Morgenstelle 18, 72076, Tübingen, Germany

    Herbert Schott

Authors
  1. Reto A. Schwendener
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Herbert Schott
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Reto A. Schwendener .

Editor information

Editors and Affiliations

  1. School of Pharmacy – Boston, MCPHS University, Boston, Massachusetts, USA

    Gerard G.M. D'Souza

Rights and permissions

Reprints and permissions

Copyright information

© 2017 Springer Science+Business Media New York

About this protocol

Cite this protocol

Schwendener, R.A., Schott, H. (2017). Liposome Formulations of Hydrophobic Drugs. In: D'Souza, G. (eds) Liposomes. Methods in Molecular Biology, vol 1522. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-6591-5_6

Download citation

  • DOI: https://doi.org/10.1007/978-1-4939-6591-5_6

  • Published:

  • Publisher Name: Humana Press, New York, NY

  • Print ISBN: 978-1-4939-6589-2

  • Online ISBN: 978-1-4939-6591-5

  • eBook Packages: Springer Protocols

Publish with us

Policies and ethics

Search

Navigation