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BioMed Research International
Volume 2013 (2013), Article ID 710502, 7 pages
http://dx.doi.org/10.1155/2013/710502
Research Article

A Polyethylenimine-Linoleic Acid Conjugate for Antisense Oligonucleotide Delivery

1Institute of Life Sciences, Jilin University, Changchun, Jilin 130023, China
2Division of Pharmaceutics, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA

Received 4 January 2013; Revised 28 April 2013; Accepted 5 May 2013

Academic Editor: Susana N. Diniz

Copyright © 2013 Jing Xie et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

A novel antisense oligonucleotide (ASO) carrier, polyethylenimine conjugated to linoleic acid (PEI-LA), was synthesized and evaluated for delivery of LOR-2501 to tumor cells. LOR-2501 is an ASO targeting ribonucleotide reductase R1 subunit (RRM1). In this study, PEI-LA was synthesized by reacting PEI (Mw ~ 800) with linoleoyl chloride. Gel retardation assay showed complete complexation between PEI-LA and LOR-2501 at N/P ratio above 8. No significant cytotoxicity was observed with these complexes at the tested dosage levels. Interestingly, at N/P ratio of >6, levels of cellular uptake of PEI-LA/LOR-2501 were double that of PEI/LOR-2501 complexes of the same N/P ratio. PEI-LA/LOR-2501 induced downregulation of 64% and 70% of RRM1 at mRNA and protein levels, respectively. The highest transfection activity was shown by PEI-LA/LOR-2501 complexes at N/P ratio of 10. Finally, using pathway specific inhibitors, clathrin-mediated endocytosis was shown to be the principle mechanism of cellular internalization of these complexes. In conclusion, PEI-LA is a promising agent for the delivery of ASOs and warrants further investigation.