In vitro membrane penetration of modified peptide nucleic acid (PNA)

Efficient cellular uptake is crucial for the success of any drug directed t owards targets inside cells. Peptide nucleic acid (PNA), a DNA analog with a promising potential as a gene-directed drug, has been shown to display sl ow membrane penetration in cell cultures. We here used liposomes as an in v itro model of cell membranes to investigate the effect on penetration of a PNA molecule colvalently modified with a lipophilic group, an adamantyl moi ety. The adamantyl attachment was found to increase the membrane-penetratio n rate of PNA three-fold, as compared to corresponding unmodified PNA. From the penetration behaviour of a number of small and large molecules we coul d conclude that passive diffusion is the mechanism for liposome-membrane pa ssage. Flow linear dichroism (LD) of the modified PNA in presence of rod-sh aped micelles, together with octanol-water distribution experiments. showed that the adamantyl-modified PNA is amphiphilic; the driving force behind t he observed increased membrane-penetration rate appears to be an accumulati on of the PNA in the lipid double layer.