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dc.contributor.advisorDesaulniers, Jean-Paul
dc.contributor.authorSalim, Lidya
dc.date.accessioned2023-03-13T15:29:54Z
dc.date.available2023-03-13T15:29:54Z
dc.date.issued2021-07-01
dc.identifier.urihttps://hdl.handle.net/10155/1581
dc.description.abstractAberrant gene expression is a hallmark of disease, so it is of great interest to develop targeted therapies that provide a means to regulate gene expression. The RNA interference pathway serves as a natural defense system against invasive genetic information and results in gene silencing by targeting and degrading mRNA. Synthetic short interfering RNAs (siRNAs) can use this endogenous machinery and have emerged as a novel class of gene-silencing therapeutics. Unfortunately, the development of RNAi therapeutics has been hindered by several challenges associated with the nature and structure of RNA. To harness their full potential, siRNAs must be chemically modified to improve their pharmacokinetic profiles. This dissertation reports the use of two bioconjugates, cholesterol and folic acid, to improve the cellular uptake and delivery of siRNAs and explores the incorporation of a novel sugar moiety within siRNAs to assess its effect on gene-silencing activity. Cholesterol has been extensively used as a delivery vector for nucleic acids. In this work, we show a novel way to functionalize siRNAs with cholesterol, via a triazole linkage, and demonstrate the efficacy of these self-delivering siRNA. Despite their promise, lipid-conjugated siRNAs tend to accumulate in areas like the liver and kidneys, so there is great interest in developing siRNA-conjugates to target other cells and tissues. Based on this, we explored the use of a folate ligand to selectively deliver siRNAs to cancer cells via the folate receptor. This receptor is highly overexpressed in numerous cancers and has become an important molecular marker in cancer research. Here, we show that centrally modified folate-siRNA conjugates display enhanced gene-silencing activity and can be selectively delivered to folate receptor-expressing cancer cells. Lastly, we explore the incorporation of a novel glucose moiety, triazole-linked to uracil at position one, in the sense or antisense strand of siRNAs. The resulting siRNA duplexes contained a single 3′-6′/2′-5′ phosphodiester linkage and achieved good gene-silencing activity. Together, this dissertation demonstrates the efficacy of several chemical modifications at improving some of the limitations associated with siRNAs, providing new avenues for the development of safe and effective RNAi therapeutics.en
dc.description.sponsorshipUniversity of Ontario Institute of Technologyen
dc.language.isoenen
dc.subjectNucleic acidsen
dc.subjectRNAien
dc.subjectsiRNAen
dc.subjectBioconjugatesen
dc.subjectDrug deliveryen
dc.titleSynthesis, characterization and biological investigation of self-delivering and modified short interfering RNAs (siRNAs)en
dc.typeDissertationen
dc.degree.levelDoctor of Philosophy (PhD)en
dc.degree.disciplineApplied Bioscienceen


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