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Clinical & Experimental Metastasis

, Volume 27, Issue 1, pp 25–34 | Cite as

Inhibition of metastasis in a murine 4T1 breast cancer model by liposomes preventing tumor cell-platelet interactions

  • Jane Wenzel
  • Reiner Zeisig
  • Iduna Fichtner
Research paper

Abstract

The interaction between circulating tumor cells and blood components, mainly platelets, plays an important role during metastasis. In this study, we prepared liposomes containing the platelet aggregation inhibitor Cilostazol (Cil-L). The objective of this study was to investigate the effect of this Cil-L on platelet aggregation and complex formation with murine 4T1 breast cancer cells in vitro and to determine their anti-metastatic potency in a spontaneous metastasis model of 4T1 breast cancer. Cil-L significantly inhibited the aggregation of platelets by up to 78% and completely abolished the complex formation of 4T1 tumor cells in the presence of activated platelets in vitro. Intravenous (i.v.) injection of Cil-L into mice significantly reduced the aggregability of mouse platelets by 60% measured ex vivo. To gain deeper insight into the mode of metastasis formation in a spontaneous metastasis model, 4T1 breast cancer cells were transplanted into the mammary fad pad of mice and metastasis to the mouse lungs was investigated with regard to tumor cell settlement and metastatic growth. We could demonstrate that the formation of pulmonary metastases was significantly reduced by 55% when mice were treated intravenously with 100 nmol Cil-L 6 h before tumor cell inoculation and then daily for 2 weeks. We conclude that Cil-L reduced metastasis by restricting the aggregability of mouse platelets, which probably prevents the interaction between circulating 4T1 tumor cells and platelets, making the Cil-L a useful tool for the inhibition of breast cancer metastasis in mice.

Keywords

Breast cancer Cilostazol Liposomes Platelet aggregation Metastasis 

Abbreviations

aPlt + Cil-L

Activated platelets + Cilostazol-liposomes

aPlt

Activated platelets

cAMP

Cyclic adenosine monophosphate

CH

Cholesterol

Cil-L

Cilostazol-encapsulating liposomes

Con-L

Control liposomes containing OPP

DCP

Dicetylphosphate

HPTLC

High performance thin layer chromatographie

NaCl

Sodiumchloride

OPP

Perifosine

PC

Phosphatidylcholine

PEG-PE

N-Methyl-(polyethyleneglycyl)2000-1,2-distearyl-s,n-glycero-3-phosphatidylethanolamine

PI

Polydispersity index

Plt

Platelets

SD

Standard deviation

Notes

Acknowledgments

This study was supported by the Federal Ministry of Education and Research of Germany (Biochance PLUS program; PTJ-BIO/0313601). We thank Prof. M. van der Giet for supporting the PhD work of J.W. at the Charite Berlin; M. Becker (MDC Berlin-Buch) for the excellent performance of the animal experiments; and Lipoid GmbH Ludwigshafen for providing us with egg phosphatidylcholine.

Conflict of interest statement

All authors confirm that they have no potential conflict of interest, including any financial, personal, or other relationships with other people or organizations within that could inappropriately influence (bias) their work.

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Copyright information

© Springer Science+Business Media B.V. 2009

Authors and Affiliations

  1. 1.Max-Delbrück-Center for Molecular Medicine Berlin-BuchBerlinGermany
  2. 2.Experimental Pharmacology and OncologyBerlin-Buch GmbH (EPO GmbH)BerlinGermany
  3. 3.Charité, Medical Clinic IV, NephrologyBerlinGermany

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