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

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.

• Authors: Raúl Ortiz, José Prados, Consolación Melguizo, José L Arias, M Adolfina Ruiz, Pablo J Alvarez, Octavio Caba, Raquel Luque, Ana Segura, Antonia Aránega
• Journal: International journal of nanomedicine (Int J Nanomedicine) Vol. 7 Pg. 95-107 ( 2012) ISSN: 1178-2013 [Electronic] New Zealand
• PMID: 22275826 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antimetabolites, Antineoplastic
• Drug Carriers
• E protein, bacteriophage X174
• Polyesters
• Viral Proteins
• polycaprolactone
• Fluorouracil

Topics

• Antimetabolites, Antineoplastic (chemistry, pharmacokinetics, pharmacology)
• Apoptosis (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Colonic Neoplasms (drug therapy, genetics, pathology, therapy)
• Drug Carriers (chemistry)
• Fluorouracil (chemistry, pharmacokinetics, pharmacology)
• Genetic Therapy (methods)
• Humans
• Membrane Potential, Mitochondrial (drug effects)
• Nanoparticles (chemistry)
• Polyesters (chemistry, pharmacology)
• Viral Proteins (administration & dosage, genetics, metabolism)