Cancer Chemotherapy and Pharmacology

, Volume 58, Issue 5, pp 607–617 | Cite as

Simultaneous sustained release of fludarabine monophosphate and Gd-DTPA from an interstitial liposome depot in rats: potential for indirect monitoring of drug release by magnetic resonance imaging

  • Ruediger E. Port
  • Christian Schuster
  • Christa R. Port
  • Peter Bachert
Original Article

Abstract

Introduction: Cytostatic depot preparations are interstitially administered for local chemotherapy and prevention of tumor recurrence. It would be of interest to monitor in patients as to when, to what extent, and exactly where, the drug is actually released. Liposomes containing a hydrophilic cytostatic and a hydrophilic contrast agent might be expected to release both agents simultaneously. If so, then drug release could be indirectly followed by monitoring contrast enhancement at the injection site. Methods: Multivesicular liposomes containing the antimetabolite fludarabine monophosphate and the magnetic resonance imaging (MRI) contrast agent Gd-DTPA were subcutaneously injected in rats and both agents were monitored at the injection site for 6 weeks by 19F nuclear magnetic resonance spectroscopy (MRS) in vivo and contrast-enhanced 1H MRI (T 1w 3D FLASH), respectively, in a 1.5-T whole-body tomograph. The MRS and MRI data were analyzed simultaneously by pharmacokinetic modeling using NONMEM. Results: During an initial lag time, the amount of drug at the injection site stayed constant while the contrast-enhanced depot volume expanded beyond the volume injected. Drug amount and depot volume then decreased in parallel. Lag time and elimination half-life were 9 and 6 days, respectively, in three animals, and were about 50% shorter in another animal where the depot split into sub-depots. Conclusion: The preliminary data in rats suggest that simultaneous release of a hydrophilic cytostatic and a hydrophilic contrast agent from an interstitial depot can be achieved by encapsulation in liposomes. Thus, there seems to be a potential for indirect drug monitoring through imaging.

Keywords

Fludarabine monophosphate Fluorine MR spectroscopy Liposomes Gd-DTPA MR imaging 

Notes

Acknowledgements

We are indebted to Dr. William E. Hull for preparatory in vitro MRS experiments, to Dr. Rainer Umathum for building the 19F/1H animal resonator, and to Dr. Volker Amelung for the pathohistological evaluation of tissue sections.

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Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  • Ruediger E. Port
    • 1
  • Christian Schuster
    • 2
  • Christa R. Port
    • 1
  • Peter Bachert
    • 2
  1. 1.Unit Pharmacology of Cancer TreatmentGerman Cancer Research CenterHeidelbergGermany
  2. 2.Department of Medical Physics in RadiologyGerman Cancer Research CenterHeidelbergGermany

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