PEG-ASO conjugates for efficient targeted delivery and migration inhibition in Cancer cell.

Antisense oligonucleotides (ASO) specifically bind target RNAs resulted in gene silencing, thereby inhibiting cancer cell growth. Chemical modification based on polyethylene glycol (PEG) usually improve resistance to nuclease degradation. However, the specificity and cellular uptake of PEG-conjugated ASOs for tumor cells is still a challenge. In this work, the folate (FA) and maleimide co-modified PEG was prepared and bound with thiol-modified anti-miRNA-21 ASO to form the FA-PEG-ASO conjugates by thiol-maleimide Michael addition. During the FA-PEG-ASO preparation process, removing tris-(2-carboxyethyl) phosphine hydrochloride (TCEP) is the key for the high yields. Cell imaging results showed FA-PEG-ASO internalized by the cells taken up ∼5 times higher than the control HO-PEG-ASO prepared by maleimide modified PEG and anti-miRNA-21 ASO. In addition, FA-PEG-ASO exhibited higher target cleavage and a greater reduction in tumor cell migration ability. Together, FA-PEG-ASO is a promising therapeutic platform.