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      International Journal of Nanomedicine (submit here)

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      5-Fluorouracil-loaded poly( ε-caprolactone) nanoparticles combined with phage E gene therapy as a new strategy against colon cancer

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          Abstract

          This work aimed to develop a new therapeutic approach to increase the efficacy of 5-fluorouracil (5-FU) in the treatment of advanced or recurrent colon cancer. 5-FU-loaded biodegradable poly( ε-caprolactone) nanoparticles (PCL NPs) were combined with the cytotoxic suicide gene E (combined therapy). The SW480 human cancer cell line was used to assay the combined therapeutic strategy. This cell line was established from a primary adenocarcinoma of the colon and is characterized by an intrinsically high resistance to apoptosis that correlates with its resistance to 5-FU. 5-FU was absorbed into the matrix of the PCL NPs during synthesis using the interfacial polymer disposition method. The antitumor activity of gene E from the phage ϕX174 was tested by generating a stable clone (SW480/12/E). In addition, the localization of E protein and its activity in mitochondria were analyzed. We found that the incorporation of 5-FU into PCL NPs (which show no cytotoxicity alone), significantly improved the drug’s anticancer activity, reducing the proliferation rate of colon cancer cells by up to 40-fold when compared with the nonincorporated drug alone. Furthermore, E gene expression sensitized colon cancer cells to the cytotoxic action of the 5-FU-based nanomedicine. Our findings demonstrate that despite the inherent resistance of SW480 to apoptosis, E gene activity is mediated by an apoptotic phenomenon that includes modulation of caspase-9 and caspase-3 expression and intense mitochondrial damage. Finally, a strongly synergistic antiproliferative effect was observed in colon cancer cells when E gene expression was combined with the activity of the 5-FU-loaded PCL NPs, thereby indicating the potential therapeutic value of the combined therapy.

          Author and article information

          Journal
          Int J Nanomedicine
          Int J Nanomedicine
          International Journal of Nanomedicine
          Dove Medical Press
          1176-9114
          1178-2013
          2012
          2012
          09 January 2012
          : 7
          : 95-107
          Affiliations
          [1 ]Institute of Biopathology and Regenerative Medicine (IBIMER)
          [2 ]Department of Pharmacy and Pharmaceutical Technology, University of Granada, Granada, Spain;
          [3 ]Department of Health Science, University of Jaén, Jaén, Spain;
          [4 ]Service of Medical Oncology, Virgen de las Nieves Hospital, Granada, Spain;
          [5 ]CSIC-Estacion Experimental del Zaidin, Department of Environmental Protection, Granada, Spain
          Author notes
          Correspondence: José Prados, Institute of Biopathology and Regenerative Medicine (IBIMER), Department of Anatomy and Embryology, School of Medicine, University of Granada, 18100 Granada, Spain, Tel +34 958 243 534, Fax +34 958 246 296, Email jcprados@ 123456ugr.es
          Article
          ijn-7-095
          10.2147/IJN.S26401
          3260954
          22275826
          81fd4b3c-4d1e-4721-a8f7-94035f60342a
          © 2012 Ortiz et al, publisher and licensee Dove Medical Press Ltd.

          This is an Open Access article which permits unrestricted noncommercial use, provided the original work is properly cited.

          History
          : 6 January 2012
          Categories
          Original Research

          Molecular medicine
          combined therapy,poly (ε-caprolactone),e gene,5-fluorouracil,colon cancer,gene therapy

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