Gemcitabine Treatment of Rat Soft Tissue Sarcoma with Phosphatidyldiglycerol-Based Thermosensitive Liposomes
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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 wordsdrug delivery gemcitabine hyperthermia phosphatidyloligoglycerol thermosensitive liposomes
dynamic light scattering
liposomes composed of DPPC/DSPC/DPPG2 50/20/30 (mol/mol)
fetal calf serum
high performance liquid chromatography
thin layer chromatography
solid gel to liquid disordered phase transition temperature
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.
- 4.Maki RG, Wathen JK, Patel SR, Priebat DA, Okuno SH, Samuels B, et al. Randomized phase II study of gemcitabine and docetaxel compared with gemcitabine alone in patients with metastatic soft tissue sarcomas: results of sarcoma alliance for research through collaboration study 002. J Clin Oncol. 2007;25(19):2755–63.PubMedCrossRefGoogle Scholar
- 5.Garcia-Del-Muro X, Lopez-Pousa A, Maurel J, Martin J, Martinez-Trufero J, Casado A, et al. Randomized phase II study comparing gemcitabine plus dacarbazine versus dacarbazine alone in patients with previously treated soft tissue sarcoma: a Spanish Group for Research on Sarcomas study. J Clin Oncol. 2011;29(18):2528–33.PubMedCrossRefGoogle Scholar
- 11.Judson I, Radford JA, Harris M, Blay JY, van Hoesel Q, Le Cesne A, et al. Randomised phase II trial of pegylated liposomal doxorubicin (DOXIL/CAELYX) versus doxorubicin in the treatment of advanced or metastatic soft tissue sarcoma: a study by the EORTC Soft Tissue and Bone Sarcoma Group. Eur J Cancer. 2001;37(7):870–7.PubMedCrossRefGoogle Scholar
- 16.Landon CD, Park J, Needham D, Dewhirst MW. Nanoscale drug delivery and hyperthermia: the materials design and preclinical and clinical testing of low temperature-sensitive liposomes used in combination with mild hyperthermia in the treatment of local cancer. Open Nanomed J. 2011;3:38–64.PubMedCrossRefPubMedCentralGoogle Scholar