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Nanotechnology for efficient delivery of short therapeutic oligonucleotides (antisense ODN and siRNA) and codelivery with chemical anticancer drugs for effective cancer therapy
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Nanotechnology for efficient delivery of short therapeutic oligonucleotides (antisense ODN and siRNA) and codelivery with chemical anticancer drugs for effective cancer therapy
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ETD_1785
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http://hdl.rutgers.edu/1782.2/rucore10002600001.ETD.000051294
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eng
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theses
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Chemistry
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Drug delivery systems
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Cancer--Treatment
Abstract
Despite great progress in recent years, efficient delivery of gene therapy or chemotherapy drugs into their target sites with minimal side effects remains one of the biggest challenges for effective cancer therapy. Co-delivery of siRNA targeted for proteins responsible for drug resistance and chemical anticancer drugs represents a promising new approach to overcome drug resistance and to make cancer therapy more effective. However, efficient co-delivery systems that can deliver siRNA and anti-cancer drugs simultaneously into cancer cells have rarely been developed.
This thesis is aimed at developing novel non-viral nanocarriers for efficient delivery of antisense ODN and siRNA and codelivery with chemical anticancer drugs for effective cancer therapy. We began by performing a systematic investigation on the efficacy of five generations of polypropyleneimine (PPI) dendrimers to provoke nanoparticle formation from antisense ODNs and then deliver the ODN nanoparticles into cancer cells (Chapter 2). We then developed a novel approach to efficiently package and deliver siRNAs into cancer cells with low generation non-toxic PPI dendrimers by using gold nanoparticles as a “labile catalytic” packaging agent (Chapter 3). Relying on the fundamental understanding gained from Chapters 2 and 3, we then continued the utilization of dendrimers and developed polyamidoamine (PAMAM) dendrimer-modified mesoporous silica nanoparticles (MSNs) as a stimuli-responsive controlled-release delivery system for a chemotherapy drug (Chapter 4). By using a non-gatekeeping approach, we demonstrated nearly zero release of doxorubicin in H2O and complete release once delivered into cancer cells. In Chapter 5, we further utilized MSNs as a codelivery system to simultaneously deliver Doxorubicin and a Bcl-2-targeted siRNA into A2780/AD human ovarian cancer cells for enhanced chemotherapy efficacy. We then investigated the effect of each component in the PAMAM-dendrimer modified MSN-based codelivery system on the cell uptake efficiency of siRNA and its intracellular release and localization (Chapter 6). We further studied the effect of temperature and different inhibitors on the cell uptake efficiency of MSN-Dox-G2 and found that MSN-Dox-G2 might internalize into cells through a non-endocytic process (Chapter 7). Finally, we demonstrated a specific cancer cell-targeted delivery by PEGylating the MSN-Dox-G2/siRNA complex and tagging it with a specific cancer-targeting group (Chapter 8).
This thesis is aimed at developing novel non-viral nanocarriers for efficient delivery of antisense ODN and siRNA and codelivery with chemical anticancer drugs for effective cancer therapy. We began by performing a systematic investigation on the efficacy of five generations of polypropyleneimine (PPI) dendrimers to provoke nanoparticle formation from antisense ODNs and then deliver the ODN nanoparticles into cancer cells (Chapter 2). We then developed a novel approach to efficiently package and deliver siRNAs into cancer cells with low generation non-toxic PPI dendrimers by using gold nanoparticles as a “labile catalytic” packaging agent (Chapter 3). Relying on the fundamental understanding gained from Chapters 2 and 3, we then continued the utilization of dendrimers and developed polyamidoamine (PAMAM) dendrimer-modified mesoporous silica nanoparticles (MSNs) as a stimuli-responsive controlled-release delivery system for a chemotherapy drug (Chapter 4). By using a non-gatekeeping approach, we demonstrated nearly zero release of doxorubicin in H2O and complete release once delivered into cancer cells. In Chapter 5, we further utilized MSNs as a codelivery system to simultaneously deliver Doxorubicin and a Bcl-2-targeted siRNA into A2780/AD human ovarian cancer cells for enhanced chemotherapy efficacy. We then investigated the effect of each component in the PAMAM-dendrimer modified MSN-based codelivery system on the cell uptake efficiency of siRNA and its intracellular release and localization (Chapter 6). We further studied the effect of temperature and different inhibitors on the cell uptake efficiency of MSN-Dox-G2 and found that MSN-Dox-G2 might internalize into cells through a non-endocytic process (Chapter 7). Finally, we demonstrated a specific cancer cell-targeted delivery by PEGylating the MSN-Dox-G2/siRNA complex and tagging it with a specific cancer-targeting group (Chapter 8).
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electronic resource
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xxix, 270 p. : ill.
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Ph.D.
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Includes bibliographical references
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by Minhua Chen
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Chen
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Minhua
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1978
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Minhua Chen
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He
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Huixin
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chair
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Huixin He
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Minko
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Tamara
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co-chair
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Tamara Minko
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Huskey
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Phillip
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Phillip Huskey
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Mendelsohn
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Richard
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Richard Mendelsohn
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Rutgers University
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Graduate School - Newark
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2009
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2009-05
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xx
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Rutgers University Electronic Theses and Dissertations
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Graduate School - Newark Electronic Theses and Dissertations
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doi:10.7282/T3FF3SJF
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ETD doctoral
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Minhua
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Minhua Chen
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I hereby grant to the Rutgers University Libraries and to my school the non-exclusive right to archive, reproduce and distribute my thesis or dissertation, in whole or in part, and/or my abstract, in whole or in part, in and from an electronic format, subject to the release date subsequently stipulated in this submittal form and approved by my school. I represent and stipulate that the thesis or dissertation and its abstract are my original work, that they do not infringe or violate any rights of others, and that I make these grants as the sole owner of the rights to my thesis or dissertation and its abstract. I represent that I have obtained written permissions, when necessary, from the owner(s) of each third party copyrighted matter to be included in my thesis or dissertation and will supply copies of such upon request by my school. I acknowledge that RU ETD and my school will not distribute my thesis or dissertation or its abstract if, in their reasonable judgment, they believe all such rights have not been secured. I acknowledge that I retain ownership rights to the copyright of my work. I also retain the right to use all or part of this thesis or dissertation in future works, such as articles or books.
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