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


Autoria(s): Ortiz, Raúl; Prados, José; Melguizo, Consolación; Arias, José L; Ruiz, M Adolfina; Alvarez, Pablo J; Caba, Octavio; Luque, Raquel; Segura, Ana; Aránega, Antonia
Data(s)

15/10/2012

15/10/2012

06/01/2012

Resumo

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.

Original research

This study was supported by the Department of Health of the Autonomous Government of Andalusia, Spain (project nos PI-0338 and PE-2008-FQM-3993).

Identificador

Ortiz R, Prados J, Melguizo C, Arias JL, Ruiz MA, Álvarez PJ, et al. 5-Fluorouracil-loaded poly(ε-caprolactone) nanoparticles combined with phage E gene therapy as a new strategy against colon cancer. Int J Nanomedicine. 2012;7:95-107

1176-9114 (Print)

1178-2013 (Online)

PMC3260954

http://hdl.handle.net/10668/569

10.2147/IJN.S26401

Idioma(s)

en

Publicador

Dove Medical Press

Relação

International journal of nanomedicine

http://www.dovepress.com/5-fluorouracil-loaded-polyepsilon-caprolactone-nanoparticles-combined--peer-reviewed-article-IJN

Direitos

Acceso abierto

Palavras-Chave #colon cancer #combined therapy #5-fluorouracil #gene therapy #E gene #poly (ε-caprolactone) #Neoplasias del Colon #Terapia de Gen #Humanos #Fluorouracilo #Nanopartículas #Antineoplásicos #Apoptosis #Medical Subject Headings::Diseases::Neoplasms::Neoplasms by Site::Digestive System Neoplasms::Gastrointestinal Neoplasms::Intestinal Neoplasms::Colorectal Neoplasms::Colonic Neoplasms #Medical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Therapeutics::Biological Therapy::Gene Therapy #Medical Subject Headings::Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans #Medical Subject Headings::Chemicals and Drugs::Heterocyclic Compounds::Heterocyclic Compounds, 1-Ring::Pyrimidines::Pyrimidinones::Uracil::Fluorouracil #Medical Subject Headings::Technology, Industry, Agriculture::Technology, Industry, and Agriculture::Manufactured Materials::Nanostructures::Nanoparticles #Medical Subject Headings::Chemicals and Drugs::Chemical Actions and Uses::Pharmacologic Actions::Therapeutic Uses::Antineoplastic Agents
Tipo

info:eu-repo/semantics/article

info:eu-repo/semantics/published

Artículo