TitleNanotechnology for efficient delivery of short therapeutic oligonucleotides (antisense ODN and siRNA) and codelivery with chemical anticancer drugs for effective cancer therapy
NameChen, Minhua (author), He, Huixin (chair), Minko, Tamara (co-chair), Huskey, Phillip (internal member), Mendelsohn, Richard (internal member), Rutgers University, Graduate School - Newark,
Drug delivery systems,
DescriptionDespite 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).
NoteIncludes bibliographical references
Noteby Minhua Chen
CollectionGraduate School - Newark Electronic Theses and Dissertations
Organization NameRutgers, The State University of New Jersey
RightsThe author owns the copyright to this work.