Hybridization and cellular uptake properties of lipophilic oligonucleotide-dendrimer conjugates

Abstract

Dendrimeric compounds were conjugated to oligonucleotides in order to improve their cellular uptake. Second and third generation lipophilic dendrimers were covalently attached either to the 5'-or 3'-end of oligonucleotides. Thermal denaturation experiments showed that the attachment of a third generation dendrimer leads to a substantial decrease in binding affinity. The considerably smaller second-generation dendrimers, however, are well tolerated. Fluorescence measurements revealed that the presence of a second-generation dendrimer leads to a marked increase in the cellular uptake of oligonucleotides.

Dendrimers in Oncology: An Expanding Horizon

“…The effect was still more pronounced for the fluorescein-labeled phosphorothioate oligonucleotide−dendrimer conjugate, which gave a 15-fold enhancement of uptake. The report suggests that the dendrimeric part of the conjugates acts as a lipophilic anchor and facilitates the penetration of the oligonucleotides through the cellular membrane …”

“…The report suggests that the dendrimeric part of the conjugates acts as a lipophilic anchor and facilitates the penetration of the oligonucleotides through the cellular membrane. 134 But, apart from this, there are still numerous problems associated with dendrimers. The most common of these are drug escape allowed by the relatively open configuration and hemolytic toxicity from peripheral -NH 2 groups.…”

Solid‐Phase Supports for Oligonucleotide Synthesis

“…However, intermediates in the synthesis of 111e were not characterized, nor were the loading of 111e or yields of oligonucleotide product determined. Oligonucleotides conjugated to a second-generation dendrimer, R 36 , were synthesized on a solid support 111f in typical isolated yields of 20% to 25% (Skobridis et al, 2005). The conjugates showed slightly higher binding affinity to the complementary oligoribonucleotides (+3 • C), and their cellular uptake was greater than that of the unmodified counterparts by a factor of 10 (PO) to 15 (PS) (Skobridis et al, 2005).…”

“…Oligonucleotides conjugated to a second-generation dendrimer, R 36 , were synthesized on a solid support 111f in typical isolated yields of 20% to 25% (Skobridis et al, 2005). The conjugates showed slightly higher binding affinity to the complementary oligoribonucleotides (+3 • C), and their cellular uptake was greater than that of the unmodified counterparts by a factor of 10 (PO) to 15 (PS) (Skobridis et al, 2005). A thio-phosphoramidate oligonucleotide modified with palmitoyl group, R 8 , was synthesized on solid support 111g and was shown to enhance the potency of telomerase inhibition (Herbert et al, 2005).…”