A Polyethylenimine-Linoleic Acid Conjugate for Antisense Oligonucleotide Delivery

Abstract EN

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.