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http://hdl.handle.net/11375/28977
Title: | Tuning the Biological Properties of Spherical Nucleic Acids with Phosphate Backbone Modified Oligonucleotides |
Authors: | Maggisano, Joseph |
Advisor: | Bujold, Katherine |
Department: | Chemistry and Chemical Biology |
Keywords: | Spherical Nucleic Acid, Oligonucleotide, Phosphate Backbone, Guanidinium |
Publication Date: | 2023 |
Abstract: | The increasing number of nucleic acid-based therapeutics demonstrates the potential to treat diseases at the genetic level. Although oligonucleotides show clinical potential, challenges remain including nuclease degradation, rapid clearance when administered systemically, low cell permeability, and limited distribution to tissues of interest. This is largely imparted by the polyanionic phosphate backbone, which produces unfavourable electrostatic interactions at cell membranes. As a result, their clinical translation is dependent on delivery technologies that improve stability, facilitate cell entry, and increase target affinity. Spherical nucleic acids (SNAs) consist of radially orienting linear nucleic acids onto a nanoparticle core, conferring them a three-dimensional, spherical architecture. These structures enter cells readily and display distinct properties that are independent of their nanoparticle core. Accordingly, we decided to replace the intrinsically anionic phosphodiester linkage of DNA with a phosphoramidate linkage (P-N), allowing us to incorporate new functionality at the phosphate backbone. With this handle, we inserted cationic and hydrophobically modified functional groups that were compatible with nanoscale architectures, giving rise to new properties relevant in biological contexts. Specifically, amine and guanidinium derivatized functional groups provided SNAs with a ~10-fold increase in cell uptake at early incubation times compared with unmodified SNAs. This demonstrates that we can tune the behaviour of SNAs with phosphate backbone modifications in a highly controlled manner. We hypothesize that the stringent control over location and placement of functional groups within the SNA framework will afford them favourable interactions at cell membranes, not only increasing their cell uptake, but also access to alternative uptake mechanisms and potency as therapeutics. |
URI: | http://hdl.handle.net/11375/28977 |
Appears in Collections: | Open Access Dissertations and Theses |
Files in This Item:
File | Description | Size | Format | |
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MAGGISANO_JOSEPH_A_202309_MSc.pdf | 3.54 MB | Adobe PDF | View/Open |
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