Abstract
Glyco-decorated spherical nucleic acids (SNAs) may be attractive delivery vehicles, emphasizing the sugar-specific effect on the outer sphere of the construct and at the same time hiding unfavorable distribution properties of the loaded oligonucleotides. As examples of such nanoparticles, tripodal sugar constituents of bleomycin were synthesized and conjugated with a fluorescence-labeled antisense oligonucleotide (AONARV7). Successive copper(I)-catalyzed azide-alkyne and strain-promoted alkyne-nitrone cycloadditions (SPANC) were utilized for the synthesis. Then, the glyco-AONARV7 conjugates were hybridized with complementary strands of a C60-based molecular spherical nucleic acid (i.e., a hybridization-mediated carrier). The formation and stability of these assembled glyco-decorated SNAs were evaluated by polyacrylamide gel electrophoresis (PAGE), UV melting profile analysis, and time-resolved fluorescence spectroscopy. Association constants were extracted from time-resolved fluorescence data. Preliminary cellular uptake experiments of the glyco-AONARV7 conjugates (120 nM solutions) and of the corresponding glyco-decorated SNAs (10 nM solutions) with human prostate cancer cells (PC3) showed an efficient uptake in each case. A marked variation in intracellular distribution was observed.
Highlights
Spherical nucleic acids (SNAs) are nanostructures consisting of an appropriate core and a densely packed layer of oligonucleotides.[1−9] Compared to the poor cellular delivery of linear oligonucleotides,[10−13] SNAs are efficiently taken up by cells via class A scavenger receptormediated endocytosis.[14,15] SNAs are more resistant toward nuclease degradation[16] and they elicit low innate immune response.[17]
We evaluated the particle size of the hybridization-mediated SNAs by dynamic light scattering (DLS) in 100 μL of aqueous 10 mmol L−1 phosphate-buffered saline (PBS), 1.1 mmol L−1 M KCl, 0.154 mol L−1 NaCl, pH 7.4
The oligonucleotide conjugates were labeled with a fluorescent dye and hybridized with complementary strands of a C60-based molecular SNA to form SNA structures surrounded by a carbohydrate sphere
Summary
Spherical nucleic acids (SNAs) are nanostructures consisting of an appropriate core (gold, silica, liposomes, proteins) and a densely packed layer of oligonucleotides.[1−9] Compared to the poor cellular delivery of linear oligonucleotides,[10−13] SNAs are efficiently taken up by cells via class A scavenger receptormediated endocytosis.[14,15] SNAs are more resistant toward nuclease degradation[16] and they elicit low innate immune response.[17]. The cell uptake studies of all of ON5−8 (120 nM) and the corresponding SNAs 2−5 (10 nM, i.e., the total oligonucleotide concentration was the same in each experiment) were carried out with PC3 cells, and the obtained data were compared with the untreated PC3 cells as controls.
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