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ndltd-OhioLink-oai-etd.ohiolink.edu-ucin12119198682021-08-03T06:12:38Z Design, Synthesis, and Structure-Bioactivity Characterization of Novel Carbohydrate-Based Polymers as Nucleic Acid Delivery Vectors LEE, CHEN-CHANG The efficient and safe carriers are the essential prerequisite in the development of gene therapies. Although many structure-biological investigations and improvements have already been completed in non-viral vectors, the relatively low gene expression and high cytotoxicity still prevent these vectors from clinical trials. Previous studies in our lab indicate that polycations containing carbohydrates and oligoamines have good gene expression and biocompatibility and the transfection efficiency is enhanced with an increase of the amine stoichiometry. However, a lack of the target-specificity of the delivery carriers may not be suitable for in vivo studies. In this dissertation, the design, synthesis, characterization, and biological investigation of new carbohydrate-based polymeric DNA delivery vectors will be addressed. These glycopolymers can be divided into three categories: a) Polymers containing 5 and 6 secondary amines between the carbohydrates; b) Hepatocyte-targeting polymers via modifications of carbohydrate substitution and linkage lengths; c) Glucose-based biodegradable polyesters.The first library was to study the effects of amine stoichiometry on the bioactivities by further increasing amine number within the polymer backbone. The results indicated that a further increase in amines cannot enhance the gene expression, but started to lower biocompatibility. Also, different structures (linear vs. branched) of the higher amine polymers can affect the bioactivities. Then, to study the structure-targeting effects, the hepatocyte-targeting polymers (targeted with β-D-galactose) were designed to have different spacer lengths and different degrees of carbohydrate substitution (DCS). The different spacer length polymers were polymerizing with various hydrophobic spacer length monomers (either malonic or galactose moieties), and the different DCS can be obtained by click reaction with various mole ratios of β-D-azido-galactose. The data showed that DCS and the spacer lengths can influence the targeting-recognition and hydrophobic linkages were shown to have a reversible relationship to the receptor recognition in HepG2 cells. DCS can be easier measured by 1H NMR integration method. Finally, the biodegradable polyester was created by polymerizing glucose with oligoethyleneamine monomers. This polyester can promote high cellular uptake, but the fast degradation was found to contribute to a low gene expression profile with HeLa cells. These polymeric structure-biological activity investigations can provide useful insights and information to elucidate the design of non-viral DNA delivery carriers. 2008-08-25 English text University of Cincinnati / OhioLINK http://rave.ohiolink.edu/etdc/view?acc_num=ucin1211919868 http://rave.ohiolink.edu/etdc/view?acc_num=ucin1211919868 unrestricted This thesis or dissertation is protected by copyright: all rights reserved. It may not be copied or redistributed beyond the terms of applicable copyright laws.
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NDLTD
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English
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NDLTD
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| author |
LEE, CHEN-CHANG
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LEE, CHEN-CHANG
Design, Synthesis, and Structure-Bioactivity Characterization of Novel Carbohydrate-Based Polymers as Nucleic Acid Delivery Vectors
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LEE, CHEN-CHANG
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LEE, CHEN-CHANG
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| title |
Design, Synthesis, and Structure-Bioactivity Characterization of Novel Carbohydrate-Based Polymers as Nucleic Acid Delivery Vectors
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| title_short |
Design, Synthesis, and Structure-Bioactivity Characterization of Novel Carbohydrate-Based Polymers as Nucleic Acid Delivery Vectors
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| title_full |
Design, Synthesis, and Structure-Bioactivity Characterization of Novel Carbohydrate-Based Polymers as Nucleic Acid Delivery Vectors
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| title_fullStr |
Design, Synthesis, and Structure-Bioactivity Characterization of Novel Carbohydrate-Based Polymers as Nucleic Acid Delivery Vectors
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| title_full_unstemmed |
Design, Synthesis, and Structure-Bioactivity Characterization of Novel Carbohydrate-Based Polymers as Nucleic Acid Delivery Vectors
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| title_sort |
design, synthesis, and structure-bioactivity characterization of novel carbohydrate-based polymers as nucleic acid delivery vectors
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University of Cincinnati / OhioLINK
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2008
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| url |
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1211919868
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AT leechenchang designsynthesisandstructurebioactivitycharacterizationofnovelcarbohydratebasedpolymersasnucleicaciddeliveryvectors
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1719432767968641024
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