Abstract
The present work explores the ability of poly(1-vinylimidazole) (PVI) to complex small interfering RNA (siRNA) silencing vascular endothelial growth factor (VEGF) and the in vitro efficiency of the formed complexes in A549 lung cancer cells. The polyplex formed was found to exhibit 66% complexation efficiency. The complexation was confirmed by gel retardation assays, FTIR and thermal analysis. The blank PVI polymer was not toxic to cells. The polyplex was found to exhibit excellent internalization and escaped the endosome effectively. The polyplex was more effective than free siRNA in silencing VEGF in lung cancer cells. The silencing of VEGF was quantified using Western blot and was also reflected in the depletion of HIF-1α levels in the cells treated with the polyplex. VEGF silencing by the polyplex was found to augment the cytotoxic effects of the chemotherapeutic agent 5-fluorouracil. Microarray analysis of the mRNA isolated from cells treated with free siRNA and the polyplex reveal that the VEGF silencing by the polyplex also altered the expression levels of several other genes that have been connected to the proliferation and invasion of lung cancer cells. These results indicate that the PVI complexes can be an effective agent to counter lung cancer.
Highlights
Gene therapy is a promising strategy that can be employed in the treatment of many hereditary disorders as well as diseases triggered by sporadic mutations including many forms of cancer
These results were confirmed by the ribogreen assay where it was observed that about 66% of small interfering RNA (siRNA) was complexed at a 4:1 ratio of PVI/siRNA
This work has demonstrated the capability of poly(1-vinylimidazole) to serve as an efficient carrier of siRNA for gene silencing
Summary
Gene therapy is a promising strategy that can be employed in the treatment of many hereditary disorders as well as diseases triggered by sporadic mutations including many forms of cancer. Viral or non-viral vectors to deliver the therapeutic oligonucleotide to the target cell has been widely explored to overcome the inherent problems associated with the administration of the naked oligonucleotide [2]. The high frequency of mutations and packing limitations associated with viral vectors necessitate the search for safer alternatives [3]. In this context, non-viral vectors have garnered interest in recent years as gene delivery vehicles. One of the widely explored non-viral polymeric carriers for gene delivery is poly(ethylene imine) (PEI), which can effectively escape from the endosomes through the “proton sponge” mechanism [4]. PEI systems are limited by their toxicity and, there is a need for less toxic but still effective gene carriers
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