Multifunctional bioreducible nanoparticles for gene therapy

MULTIFUNCTIONAL BIOREDUCIBLE NANOPARTICLES FORGENE THERAPY byJING LIDecember 2012Advisor: Dr. David OupickýMajor: Pharmaceutical SciencesDegree: Doctor of PhilosophyGene therapy is a promising therapeutic strategy to treat diseases causedby single or multiple gene mutations. Non-viral gene delivery vectors exhibitmany advantages over viral vectors, including enhanced safety, versatility inchoosing different types of therapeutic nucleic acids, and ease of formulation.However, low transgene efficiency and lack of targeting ability remain majorchallenges. Bioreducible polyplexes (polyelectrolyte complexes of disulfide-containing polycations and nucleic acids) utilize the redox potential gradientexisting between extracellular space and intracellular environment as aphysiological stimulus to enhance delivery of therapeutic nucleic acids to thesubcellular space. Bioreducible containing polyplexes undergo intracellularreduction mediated GSH, which results in fast disassembly of the polyplexes anddegradation of the delivery vector, leading to increased transfection efficiencyand decreased cytotoxicity.