The synthesis and incorporation of a tosylated phosphoramidite linker containing a disulfide bond is described. Incorporation of the linker into short DNA and RNA oligomers proceeded efficiently using automated solid phase synthesis. Treatment of the support bound oligonucleotide followed by cleavage from the solid support provided a variety of common functional handles, expanding the strategies of bifunctional modification of synthetic oligonucleotides for conjugation applications.
The introduction of chemical modifications on the nucleic acid scaffold has allowed for the progress of antisense oligonucleotides (ASOs) in the clinic for the treatment of a variety of disorders. In contribution to the repertoire of gene‐silencing nucleic acid modifications, herein we report the synthesis and incorporation of C5‐propynyl arabinouridine (araUP) and arabinocytidine (araCP) into mixed‐base ASOs containing a pyrimidine core. Substitution of the core with araUP and araCP resulted in stabilization of the duplex formed with RNA but not with DNA. Similar results were obtained with ASOs bearing phosphorothioate linkages or methoxyethyl (MOE) wings in a gapmer design. All modified ASOs were compatible with E. coli RNase H mediated degradation of target RNA. Substitution of DNA for araUP and araCP in the central portion of a gapmer with MOE wings demonstrated improved nuclease resistance. These results suggest C5‐modified arabinonucleic acids may serve as a potential chemical modification for therapeutic ASOs.
Gene
therapy holds great promise for the treatment of acquired
genetic disorders such as cancer with reduced side effects compared
to chemotherapy. For gene therapy to be successful, it is crucial
to develop efficient and nontoxic gene carriers to overcome the poor in vivo stability and low cellular uptake of nucleic acid-based
therapeutic agents. Here, we report a new and versatile approach exploring
a combination of hydrophobic modifications and dual-stimuli-responsive
degradation (SRD) for controlled gene delivery with amphiphilic block
copolymer-based nanocarriers. The block copolymer, synthesized by
atom transfer radical polymerization, is designed with an acid-labile
acetal linkage at the block junction and a pendant disulfide group
in the hydrophobic block. The incorporation of labile linkages enables
both disulfide-core-cross-linking and dual-location dual-acid/reduction-responsive
degradation (DL-DSRD). Furthermore, the disulfide linkages integrated
as hydrophobic moieties facilitate the nucleic acids to condense into
nanometer-sized micelleplexes through electrostatic interactions of
pendant dimethylamino groups with the anionic phosphate groups of
the nucleic acids. Our preliminary results demonstrate that the DL-DSRD
approach through hydrophobic modification is a robust platform in
the development of gene delivery systems with enhanced colloidal stability,
reduced cytotoxicity, and improved gene transfection efficiency.
The chemical and self‐assembly properties of nucleic acids make them ideal for the construction of discrete structures and stimuli‐responsive devices for a diverse array of applications. Amongst the various three‐dimensional assemblies, DNA tetrahedra are of particular interest, as these structures have been shown to be readily taken up by the cell, by the process of caveolin‐mediated endocytosis, without the need for transfection agents. Moreover, these structures can be readily modified with a diverse range of pendant groups to confer greater functionality. This minireview highlights recent advances related to applications of this interesting DNA structure including the delivery of therapeutic agents ranging from small molecules to oligonucleotides in addition to its use for sensing and imaging various species within the cell.
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