Phosphorothioate and normal oligodeoxyribonucleotides with 5′-linked acridine: characterization and preliminary kinetics of cellular uptake

Pressure-mediated oligonucleotide transfection of rat and human cardiovascular tissues

“…In fact, pressure has been found to alter both the fluid phase of biological membranes and the organization of membrane proteins and cytoskeletal elements, and these effects may be particularly important in protein-rich areas of cell membranes involved in channel formation or transmembrane transport (24,25). Hydrostatic pressure has also been documented to influence both sodium and potassium transport as well as Mg In vitro, simple ODN uptake is believed to proceed via receptor-mediated endocytosis that is associated consequently with lysosomal degradation of most of the ODN (27)(28)(29). Incorporation of ODN into cationic lipid or HVJ-liposome complexes has been shown to enhance nuclear localization of ODN in vitro and may improve antisense effect (30,31).…”

Oligodeoxynucleotide analogs with 5′‐linked anthraquinone

“…The choice of base sequence of the ODN and/or the type of ODN analog would depend on the target sequence in the target gene chosen. The results of inhibition by the S-oe-rev sequence in an in vitro T-cell viral gag protein assay have been compared with the same sequence 5'-linked to acridine [13] and anthraquinone. The latter was the most effective (10-fold vs unlinked sequence)at inhibiting HIV expression [31].…”

“…The other concerns the fact that although a cell surface receptor protein that may be involved in ODN transport has recently been identified [11,12], the S-ODNs are very slowly transported by this mechanism [11,13]. Thus, for both these reasons, cost and cellular uptake, there is a need to increase the potency of the antisense compounds.…”

“…Our strategy is to attach groups onto oligos at the 5'-terminus using the intermediate linked phosphoramidite synthons in the automatic synthesizer [13,26]. This is the most efficient approach since the 3'-terminus is attached to the solid support, and the entire synthesis occurs in the synthesizer.…”

“…In the case of the 9-aminoacridine bond, which is susceptible to cleavage by NH4OH, substitution of NaOH prevents cleavage of the linked group [27,28]. We have previously attached acridines using these methods [13,26], and describe here the products containing anthraquinones ( fig.l). This group was chosen because it is a potential radicalproducing moiety, that does not necessarily require the presence of a metal ion or optical activation, and can act very much like a series of well-known radical-producing anti-cancer drugs [29], such as adriamycin.…”