Overcoming cisplatin resistance of ovarian cancer cells by targeted liposomes in vitro.

The clinical application of cisplatin to treat solid tumours is often limited by the development of tumour cell resistance against this cytostatic agent. Although liposomal carriers of cisplatin are currently in clinical development, approaches to functionally overcome cisplatin resistance by liposomes have hardly been reported. We prepared PEGylated cisplatin-containing liposomes with diameters of about 110 nm and targetability to transferrin receptors (TfR) to correlate cisplatin cell uptake with cytotoxicity in sensitive and cisplatin resistant ovarian cancer cells A2780 compared to the free drug. Whereas the cell entry of free cisplatin was reduced by factor 4 after 24h in resistant cells, liposomal uptake was similar in both cell lines and not affected by resistance. Cytotoxicity was clearly related to intracellular platinum levels, which were even higher for liposomal vs. free cisplatin in the resistant cells after 24, 48, and 72 h and slightly lower in the sensitive cells. However, TfR targeting was of less impact on activity in comparison to non-targeted liposomes. Detection of cellular ATP levels within 24h allowed postulations on the intracellular fate of the liposomes. Altogether, this study strongly supports approaches to overcome cisplatin resistance by a liposomal application of the drug.

[1]  U. Jaehde,et al.  Cellular accumulation and cytotoxicity of macromolecular platinum complexes in cisplatin-resistant tumor cells. , 2008, Journal of controlled release : official journal of the Controlled Release Society.

[2]  R. Vile,et al.  Phase I-II study of pegylated liposomal cisplatin (SPI-077) in patients with inoperable head and neck cancer. , 2001, Annals of oncology : official journal of the European Society for Medical Oncology.

[3]  T. Boulikas,et al.  First safety and response results of a randomized phase III study with liposomal platin in the treatment of advanced squamous cell carcinoma of the head and neck (SCCHN). , 2007, Anticancer research.

[4]  A. Pa,et al.  Cellular pharmacology of cisplatin: perspectives on mechanisms of acquired resistance. , 1990 .

[5]  Kazuo Maruyama,et al.  Effective anti-tumor activity of oxaliplatin encapsulated in transferrin-PEG-liposome. , 2008, International journal of pharmaceutics.

[6]  I. Herskowitz,et al.  Uptake of the anticancer drug cisplatin mediated by the copper transporter Ctr1 in yeast and mammals , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[7]  H. Shmeeda,et al.  Pros and Cons of the Liposome Platform in Cancer Drug Targeting , 2006, Journal of liposome research.

[8]  E. Pereira-Maia,et al.  Preparation and cytotoxicity of cisplatin-containing liposomes. , 2007, Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas.

[9]  Q. Ping,et al.  Targeted delivery of doxorubicin using stealth liposomes modified with transferrin. , 2009, International journal of pharmaceutics.

[10]  Carsten Denkert,et al.  Hyperactivation of the insulin-like growth factor receptor I signaling pathway is an essential event for cisplatin resistance of ovarian cancer cells. , 2009, Cancer research.

[11]  S. Bates,et al.  New and Revised Concepts in Multidrug Resistance , 2006 .

[12]  U. Bakowsky,et al.  Targetability of novel immunoliposomes prepared by a new antibody conjugation technique. , 1999, International journal of pharmaceutics.

[13]  J. Minna,et al.  Epidermal Growth Factor Receptor Pathway Analysis Identifies Amphiregulin as a Key Factor for Cisplatin Resistance of Human Breast Cancer Cells* , 2008, Journal of Biological Chemistry.

[14]  N Thatcher,et al.  Phase II study of SPI-77 (sterically stabilised liposomal cisplatin) in advanced non-small-cell lung cancer , 2006, British Journal of Cancer.

[15]  K. Edwards,et al.  Use of a passive equilibration methodology to encapsulate cisplatin into preformed thermosensitive liposomes. , 2008, International journal of pharmaceutics.

[16]  G. Samimi,et al.  The Copper Influx Transporter Human Copper Transport Protein 1 Regulates the Uptake of Cisplatin in Human Ovarian Carcinoma Cells , 2004, Molecular Pharmacology.

[17]  Michael Wiese,et al.  Comparison of the Usefulness of the MTT, ATP, and Calcein Assays to Predict the Potency of Cytotoxic Agents in Various Human Cancer Cell Lines , 2004, Journal of biomolecular screening.

[18]  J. Marin,et al.  Overcoming cisplatin resistance in vitro by a free and liposome‐encapsulated bile acid derivative: BAMET‐R2 , 2000, International journal of cancer.

[19]  U. Jaehde,et al.  Determination of platinum complexes in clinical samples by a rapid flameless atomic absorption spectrometry assay. , 1999, Therapeutic drug monitoring.

[20]  B. de Kruijff,et al.  High Cytotoxicity of Cisplatin Nanocapsules in Ovarian Carcinoma Cells Depends on Uptake by Caveolae-Mediated Endocytosis , 2009, Clinical Cancer Research.

[21]  T. Boulikas,et al.  Pharmacokinetics and adverse reactions of a new liposomal cisplatin (Lipoplatin): phase I study. , 2005, Oncology reports.

[22]  Z. Siddik,et al.  Cisplatin: mode of cytotoxic action and molecular basis of resistance , 2003, Oncogene.

[23]  M. Gottesman,et al.  Endocytic recycling compartments altered in cisplatin-resistant cancer cells. , 2006, Cancer research.

[24]  G. Peterson,et al.  A simplification of the protein assay method of Lowry et al. which is more generally applicable. , 1977, Analytical biochemistry.

[25]  Joseph Kost,et al.  Ultrasound triggered release of cisplatin from liposomes in murine tumors. , 2009, Journal of controlled release : official journal of the Controlled Release Society.

[26]  I. Pastan,et al.  Decreased accumulation of [14c]carboplatin in human cisplatin‐resistant cells results from reduced energy‐dependent uptake , 2000, Journal of cellular physiology.

[27]  U. Jaehde,et al.  Altered localisation of the copper efflux transporters ATP7A and ATP7B associated with cisplatin resistance in human ovarian carcinoma cells , 2008, BMC Cancer.

[28]  B. Ames,et al.  The role of polyamines in the neutralization of bacteriophage deoxyribonucleic acid. , 1960, The Journal of biological chemistry.