Percutaneous absorption of antisense phosphorothioate oligonucleotide in vitro

Antisense oligonucleotides seem to provide a promising new tool for the therapy. Choi et al. (1995) reported antisense phosphorothioate oligonucleotides (PS-ODN, 25 mer) complementary to TGF-beta mRNA designed for scar formation inhibitor to eliminate scars, which was caused by undesired collagen deposition due to overexpression of TGF-beta, in wounded skin. PS-ODN were evaluated in vitro for skin penetration using normal and tape-stripped damaged rat skin. The in vitro skin transports were carried out with partially modified PS-ODN (6S) and fully modified PS-ODN (25S). The cumulative amount of PS-ODN (6S) penetrated through normal rat skin was 0.234+/-0.041 mu g/cm(2) and that of tape-stripped damaged rat skin was 1.077+/-0.301 mu g/cm(2) over 8 hrs. PS-ODN (25S) can not be found in receptor medium through normal skin due to high molecular weight (Mol.Wt.=8,000) and polyanionic charge. However, the cumulative amount of PS-ODN (25S) penetrated across damaged rat skin in PBS was 0.340+/-0.296 mu g/cm(2) over 8 hrs. The absense of dermis raised the cumulative amount of PS-ODN (6S) penetrated through rat skin. And the fluxes of PS-ODN (6S) and PS-ODN (25S) at 8hrs across damaged rat skin were 133.63+/-37.67 ng/cm(2) h, and 42.50+/-36.95 ng/cm(2) h, respectively. While PS-ODN (25S) was stable in 10% heat inactivated fetal bovine serum (FBS) during 24 hrs, PS-ODN (6S) was less stable than PS-ODN (25S), but was markedly stable than unmodified phosphodiester. It is suggested that the cumulative amount of PS-ODN (6S) penetrated through damaged rat skin is larger than that of PS-ODN (25S) since the former is easier to degrade by nuclease than the latter and then is apt to penetrate into skin. Thus, PS-ODN represents a logical candidate for further evaluation due to the potential for delivery into the wounded skin.