Delivery of steric block morpholino oligomers by (R-X-R)(4) peptides: structure–activity studies

Abes, Rachida; Moulton, Hong M.; Clair, Philippe; Yang, Sung-Tae; Abes, Said; Melikov, Kamran; Prevot, Paul; Youngblood, Derek S.; Iversen, Patrick L.; Chernomordik, Leonid V.; Lebleu, Bernard

In conclusion, our studies support the now wellaccepted scheme of cellular internalization involving initial binding to cell surface glycosaminoglycans, endocytosis and entrapment within cytoplasmic vesicles. Most of the material unfortunately remains segregated in endocytic vesicles even for the most active of our conjugates and efforts should now be geared at improving endosomal escape. Model systems described here might turn rather useful in future SAR studies if pH-dependent liposome destabilization can be correlated with splicing correction efficiency. The most active conjugates will also have to be monitored for their biodisponibility, metabolic stability and biological activity in animal models.