A Polyethylenimine-Linoleic Acid Conjugate for Antisense Oligonucleotide Delivery

作者：Xie, Jing; Teng, Lesheng; Yang, Zhaogang; Zhou, Chenguang; Liu, Yang; Yung, Bryant C.; Lee, Robert J.^*

来源：Biomed Research International, 2013, 2013: 710502.

DOI：10.1155/2013/710502

• I CLINICAL-TRIAL
• GENE TRANSFECTION
• CELLULAR UPTAKE
• NANOPARTICLES
• THERAPEUTICS
• COMPLEXES
• SYSTEMS
• VECTOR
• CELLS
• VITRO

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 similar to 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.

• 出版日期2013
• 单位吉林大学