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.
Highlights
There is considerable pharmaceutical interest in the use of synthetic oligonucleotides that intervene in the process of gene expression, such as antisense oligonucleotides[1] or siRNAs.[2]
Synthesis of the oligonucleotide dendrimer conjugates The dendrons 1 and 2 were prepared following the method of Frėchet.[18]
The conversion of dendrimers 1 and 2 into activated N-hydroxy succinimide (NHS-) esters is shown in Scheme 1
Summary
There is considerable pharmaceutical interest in the use of synthetic oligonucleotides that intervene in the process of gene expression, such as antisense oligonucleotides[1] or siRNAs.[2]. The present paper describes the synthesis of various 5′- and 3′-oligonucleotide-dendrimer conjugates, their hybridization properties and uptake by T24 cells. For the synthesis of 3′-oligonucleotide-dendrimer conjugates, a dendrimer-derived solid support was prepared.
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