Overview  |  Gene delivery controlled by redox potential gradients  |  Layer-by-layer DNA films for gene delivery | Stimulus-controlled drug delivery from nanoporous inorganic nanoparticles

Self-assembly complexes of nucleic acids and polycations (polyplexes) are investigated as promising delivery vectors for a variety of nucleic acid therapeutics. One of the several stimuli, which has been utilized for improving the efficiency of nucleic acid delivery, is the redox potential gradient existing between extracellular and intracellular environments. The existence of a high redox potential gradient between oxidizing extracellular space and the reducing environment of subcellular organelles has been exploited by incorporating disulfide bonds into the structure of the delivery vectors to provide them with the capability to release the therapeutic nucleic acids selectively in the subcellular reducing space.

Our interests range from the synthesis of novel reducible polycations, understanding the mechanism of polyplex disassembly in response to applying the redox stimulus, all the way to understanding the effects of intracellular reduction on cytotoxicity and transfection activity of the polyplexes. In addition, we are investigating the possibility of exploiting altered redox cellular states associated with pathological states, such as Bcl-2 overexpression in various cancers, for improving the activity and selectivity of transfection of redox-responsive polyplexes.

Collaborators

Prof. Guangzhao Mao, Prof. Ken Howard

Representative Publications

D. S. Manickam, A. Hirata, D. A. Putt, L. H. Lash, F. Hirata, D. Oupicky. "Overexpression of Bcl-2 as a proxy redox stimulus to enhance activity of non-viral redox-responsive delivery vectors." Biomaterials, 2008, 29, 2680-2688. (Abstract)

Y. You, D. Soundara Manickam, Q. Zhou, D. Oupicky. "Dually responsive multiblock copolymers via RAFT polymerization: Synthesis of temperature- and redox-responsive copolymers of PNIPAM and PDMAEMA." Macromolecules, 2007, 40, 8617-8624. (Abstract)

Y. You, D. Soundara Manickam, Q. Zhou, D. Oupický. "Reducible poly(2-dimethyl aminoethyl methacrylate): Synthesis, cytotoxicity, and gene delivery activity." Journal of Controlled Release, 2007, 122, 217-225. (Abstract)