Tuning G-Quadruplex Nanostructures with Lipids. Towards Designing Hybrid Scaffolds for Oligonucleotide Delivery |
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Authors: | Santiago Grijalvo Anna Clua Marc Eres Raimundo Gargallo Ramon Eritja |
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Affiliation: | 1.Institute for Advanced Chemistry of Catalonia (IQAC-CSIC), Jordi Girona 18-26, E-08034 Barcelona, Spain; (S.G.); (A.C.); (M.E.);2.Networking Center on Bioengineering, Biomaterials and Nanomedicine (CIBER BBN), Jordi Girona 18-26, E-08034 Barcelona, Spain;3.Department of Chemical Engineering and Analytical Chemistry, University of Barcelona, Martí i Franquès 1-11, E-08028 Barcelona, Spain; |
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Abstract: | Two G-quadruplex forming oligonucleotides d(TG4T)4 and d(TG6T)4] were selected as two tetramolecular quadruplex nanostructures because of their demonstrated ability to be modified with hydrophobic molecules. This allowed us to synthesize two series of G-quadruplex conjugates that differed in the number of G-tetrads, as well as in the terminal position of the lipid modification. Both solution and solid-phase syntheses were carried out to yield the corresponding lipid oligonucleotide conjugates modified at their 3′- and 5′-termini, respectively. Biophysical studies confirmed that the presence of saturated alkyl chains with different lengths did not affect the G-quadruplex integrity, but increased the stability. Next, the G-quadruplex domain was added to an 18-mer antisense oligonucleotide. Gene silencing studies confirmed the ability of such G-rich oligonucleotides to facilitate the inhibition of target Renilla luciferase without showing signs of toxicity in tumor cell lines. |
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Keywords: | antisense oligonucleotides circular dichroism G-quadruplex gene delivery gene transfection lipids luciferase nucleic acid conjugates solid-phase solution-phase |
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