Pharmaceutical Research

, Volume 31, Issue 9, pp 2276–2286 | Cite as

Gemcitabine Treatment of Rat Soft Tissue Sarcoma with Phosphatidyldiglycerol-Based Thermosensitive Liposomes

  • Simone Limmer
  • Jasmin Hahn
  • Rebecca Schmidt
  • Kirsten Wachholz
  • Anja Zengerle
  • Katharina Lechner
  • Hansjörg Eibl
  • Rolf D. Issels
  • Martin HossannEmail author
  • Lars H. Lindner
Research Paper



The pyrimidine analogue gemcitabine (dFdC) is frequently used in the treatment of patients with solid tumors. However, after i.v. application dFdC is rapidly inactivated by metabolization. Here, the potential of thermosensitive liposomes based on 1,2-dipalmitoyl-sn-glycero-3-phosphodiglycerol (DPPG2-TSL) were investigated as carrier and targeting system for delivery of dFdC in combination with local hyperthermia (HT).


DPPG2-TSL were prepared by the lipid film hydration and extrusion method and characterized by dynamic light scattering, thin layer chromatography, phosphate assay and HPLC. In vivo experiments were performed in Brown Norway rats with a syngeneic soft tissue sarcoma. Local HT treatment was performed by light exposure.


DPPG2-TSL were stable at 37°C in serum and showed a temperature dependent dFdC release >40°C. Plasma half-life of dFdC was strongly increased from 0.07 h (non-liposomal) to 0.53 h (liposomal, vesicle size 105 nm) or 2.59 h (liposomal, 129 nm). Therapy of BN175 tumors with dFdC encapsulated in DPPG2-TSL + HT showed significant improvement in tumor growth delay compared to non-liposomal dFdC without HT (p < 0.05), non-liposomal dFdC with HT (p < 0.01), and liposomal dFdC without HT (p < 0.05), respectively.


Gemcitabine encapsulated in DPPG2-TSL in combination with local HT is a promising tool for the treatment of solid tumors. Therefore, these encouraging results ask for further investigation and evaluation.

Key words

drug delivery gemcitabine hyperthermia phosphatidyloligoglycerol thermosensitive liposomes 





gemcitabine triphosphate


dynamic light scattering






liposomes composed of DPPC/DSPC/DPPG2 50/20/30 (mol/mol)




fetal calf serum


high performance liquid chromatography


local hyperthermia




internal standard








thin layer chromatography


solid gel to liquid disordered phase transition temperature


thermosensitive liposomes


Acknowledgments And Disclosures

The authors gratefully acknowledge the help of E. Wagner (Department of Pharmaceutical Biology-Biotechnology, Ludwig-Maximilians University, Munich, Germany) for providing facilities.

The research leading to these results has received funding from the European Union Seventh Framework Programme (FP7/2007-2013) under grant agreement n° 603028 (iPaCT project).

Chemical compounds studied in this study: DSPC (Pubmed CID 94190), DPPC (Pubmed CID 452110), DPPG2 (no Pubmed CID available, CAS 495403-05-9), dFdC (Pubmed CID: 60749).

The authors alone are responsible for the content and writing of the paper.

Supplementary material

11095_2014_1322_MOESM1_ESM.doc (404 kb)
ESM 1 (DOC 404 kb)


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Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Simone Limmer
    • 1
    • 2
  • Jasmin Hahn
    • 1
  • Rebecca Schmidt
    • 1
  • Kirsten Wachholz
    • 1
  • Anja Zengerle
    • 1
  • Katharina Lechner
    • 1
    • 2
  • Hansjörg Eibl
    • 3
  • Rolf D. Issels
    • 1
    • 2
  • Martin Hossann
    • 1
    • 2
    • 4
    Email author
  • Lars H. Lindner
    • 1
    • 2
  1. 1.Department of Internal Medicine IIIUniversity Hospital Munich Ludwig-Maximilians UniversityMunichGermany
  2. 2.CCG Tumor Therapy through Hyperthermia, Helmholtz Zentrum MünchenGerman Research Center for Environmental HealthMunichGermany
  3. 3.Max Planck Institute for Biophysical ChemistryGoettingenGermany
  4. 4.Medizinische Klinik und Poliklinik IIIKlinikum der Universität MünchenMunichGermany

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