PERCUTANEOUS PENETRATION OF METHYL PHOSPHONATE ANTISENSE OLIGONUCLEOTIDES

A series of antisense methyl phosphonate oligonucleotides (MPOs) were evaluated in vitro for skin penetration and retention using either hairless mouse or human cadaver skin. Several skin penetration enhancers were used to promote uptake of MPOs ranging in molecular weight from 1834 to 5500. In general, as the molecular weight of the MPOs increased, the penetration rate decreased. Tape stripping experiments with both hairless mouse skin and human cadaver skin indicated that the stratum corneum is the primary barrier to penetration. Comparison of a 14-mer MPO and the same MPO modified by the introduction of one negative charge (phosphate linkage) per molecule reduced the skin permeability by about 10-fold. The amount of MPO retained in the dermis at the end of the 24 h permeation experiments indicated that most of the compounds were able to reach a nominal target concentration of 1.0 mu M. The largest MPO tested (18-mer, Mol. Wt 5500) gave the least amount of material penetrating through human cadaver skin, but depending on the vehicle, was retained in nearly sufficient amounts in the target tissues (dermis). Thus, the 18-mer represents a logical candidate for further evaluation due to the potential for delivery into the target tissue with limited systemic exposure.