5-Fluorouracil-loaded poly(ε-caprolactone) nanoparticles combined with phage E gene therapy as a new strategy against colon cancer
Raúl Ortiz1,3, José Prados1, Consolación Melguizo1, José L Arias2, M Adolfina Ruiz2, Pablo J Álvarez1, Octavio Caba1,3, Raquel Luque4, Ana Segura5, Antonia Aránega11Institute of Biopathology and Regenerative Me...
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Dove Medical Press
2012
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oai:doaj.org-article:8e5f1b43c5304d7a9962a9da7d79a5ea2021-12-02T02:48:33Z5-Fluorouracil-loaded poly(ε-caprolactone) nanoparticles combined with phage E gene therapy as a new strategy against colon cancer1176-91141178-2013https://doaj.org/article/8e5f1b43c5304d7a9962a9da7d79a5ea2012-01-01T00:00:00Zhttp://www.dovepress.com/5-fluorouracil-loaded-polyepsilon-caprolactone-nanoparticles-combined--a9017https://doaj.org/toc/1176-9114https://doaj.org/toc/1178-2013Raúl Ortiz1,3, José Prados1, Consolación Melguizo1, José L Arias2, M Adolfina Ruiz2, Pablo J Álvarez1, Octavio Caba1,3, Raquel Luque4, Ana Segura5, Antonia Aránega11Institute of Biopathology and Regenerative Medicine (IBIMER), 2Department of Pharmacy and Pharmaceutical Technology, University of Granada, Granada, Spain; 3Department of Health Science, University of Jaén, Jaén, Spain; 4Service of Medical Oncology, Virgen de las Nieves Hospital, Granada, Spain; 5CSIC-Estacion Experimental del Zaidin, Department of Environmental Protection, Granada, SpainAbstract: 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.Keywords: colon cancer, combined therapy, 5-fluorouracil, gene therapy, E gene, poly (ε-caprolactone)Ortiz RPrados JMelguizo CArias JLRuíz MAÁlvarez PJCaba OLuque RSegura AAránega ADove Medical PressarticleMedicine (General)R5-920ENInternational Journal of Nanomedicine, Vol 2012, Iss default, Pp 95-107 (2012) |
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Medicine (General) R5-920 |
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Medicine (General) R5-920 Ortiz R Prados J Melguizo C Arias JL Ruíz MA Álvarez PJ Caba O Luque R Segura A Aránega A 5-Fluorouracil-loaded poly(ε-caprolactone) nanoparticles combined with phage E gene therapy as a new strategy against colon cancer |
| description |
Raúl Ortiz1,3, José Prados1, Consolación Melguizo1, José L Arias2, M Adolfina Ruiz2, Pablo J Álvarez1, Octavio Caba1,3, Raquel Luque4, Ana Segura5, Antonia Aránega11Institute of Biopathology and Regenerative Medicine (IBIMER), 2Department of Pharmacy and Pharmaceutical Technology, University of Granada, Granada, Spain; 3Department of Health Science, University of Jaén, Jaén, Spain; 4Service of Medical Oncology, Virgen de las Nieves Hospital, Granada, Spain; 5CSIC-Estacion Experimental del Zaidin, Department of Environmental Protection, Granada, SpainAbstract: 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.Keywords: colon cancer, combined therapy, 5-fluorouracil, gene therapy, E gene, poly (ε-caprolactone) |
| format |
article |
| author |
Ortiz R Prados J Melguizo C Arias JL Ruíz MA Álvarez PJ Caba O Luque R Segura A Aránega A |
| author_facet |
Ortiz R Prados J Melguizo C Arias JL Ruíz MA Álvarez PJ Caba O Luque R Segura A Aránega A |
| author_sort |
Ortiz R |
| title |
5-Fluorouracil-loaded poly(ε-caprolactone) nanoparticles combined with phage E gene therapy as a new strategy against colon cancer |
| title_short |
5-Fluorouracil-loaded poly(ε-caprolactone) nanoparticles combined with phage E gene therapy as a new strategy against colon cancer |
| title_full |
5-Fluorouracil-loaded poly(ε-caprolactone) nanoparticles combined with phage E gene therapy as a new strategy against colon cancer |
| title_fullStr |
5-Fluorouracil-loaded poly(ε-caprolactone) nanoparticles combined with phage E gene therapy as a new strategy against colon cancer |
| title_full_unstemmed |
5-Fluorouracil-loaded poly(ε-caprolactone) nanoparticles combined with phage E gene therapy as a new strategy against colon cancer |
| title_sort |
5-fluorouracil-loaded poly(ε-caprolactone) nanoparticles combined with phage e gene therapy as a new strategy against colon cancer |
| publisher |
Dove Medical Press |
| publishDate |
2012 |
| url |
https://doaj.org/article/8e5f1b43c5304d7a9962a9da7d79a5ea |
| work_keys_str_mv |
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