The goal of this application is to evaluate the hypothesis that the contents of vesicles (liposomes) made of redox-responsive phospholipids can be efficiently released upon liposome interaction with a specific quinone reductase enzyme that is highly concentrated in the majority of cancer tumor tissues, namely, NAD(P)H:quinone oxidoreductase type 1 (NQO1, DT-diaphorase). Demonstration of this will allow for the future development of an unprecedented group of redox-sensitive liposomes that are structurally optimized to preferentially accumulate in tumors and deliver their contents in a site-specific manner, as the result of their being opened in response to the overexpressed reductase activities in cancer tumors. Highly specific destabilization of the quinone reductase-responsive liposomes is proposed to occur by selective, enzyme-catalyzed reduction of stabilizing quinone subunits of lipids composing the liposomes. Reduction of the quinone groups leads to cleavage of the covalent link between the quinone and the phospholipid in the liposome bilayer, yielding phosphatidylethanolamine lipids that are unable to sustain bilayers. Enzyme-specific reduction leads to destruction of the liposome and release of its contents.
Specific Aims to evaluate the hypothesis include that of: 1) developing synthetically engineered quinone subunits having fast speeds of NQO1-catalyzed reduction and self-cleavage so as to yield a high rate for the overall NQO1-stimulated process;and 2) making quinone-lipid liposomes capable of rapid NQO1-activated destruction by optimizing the interaction of NQO1 with the quinone stabilizing subunits.
These Aims will be achieved by completion of a set of carefully designed experimental Objectives that address the synthesis of quinone-lipids having thermodynamic reduction values and self-cleavage rates that are optimal for enzymatic destruction and the formulation of liposomes (composition of lipids) that leads to efficient NQO1 interaction with quinone subunits. This project directly addresses the development of a class of technologies with the potential to treat an important disease, cancer, as well as inflammatory tissue diseases, such as rheumatoid arthritis, that have associated with them overexpressed reductase enzymes. The methods and materials to be developed during this work are directly applicable to the missions of the Agency Institutes, including those of the National Institute of Biomedical Imaging and Bioengineering, the National Cancer Institute, and the National Eye Institute.
This research targets the development of a responsive nanoscopic system capable of containing drugs and then delivering them upon stimulation by the presence of a specific protein associated with cancer tumors. The responsive system has the potential to provide significantly more efficient chemotherapeutic treatment of cancer tumors with fewer side effects in comparison to the current, commercially available nanoscopic delivery systems. The long-term impact of the protein-responsive delivery system is great, for roughly 6 million deaths are attributed to cancer each year.
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