Therapeutic In Vivo Synthetic Chemistry: Cancer Treatment by In Mice Metal-Catalized Reaction

Abstract

The long-term goal of our research is to develop the working tools and methodologies that will form the foundation of “Therapeutic In Vivo Synthetic Chemistry”. The main benefit of this approach is that synthetic transformations can be directly performed at target regions within the body to generate molecules that elicit localized biological effects. This method should largely circumvent off-target binding and instability issues associated with current drug administration techniques. In these years, we have engaged this topic through the usage of glycosylated artificial metalloenzymes, where the primary aim is to exploit the chemoselectivity of embedded, non-natural transition metal catalysts for the synthesis/release of bioactive molecules. Thus, we developed the albumin-based artificial metalloenzymes with various transition metal complexes, of which metals are efficiently protected inside the hydrophobic pocket of albumin, hence various transition metal-catalyzed transformation could be now possible in cells, mice, or even plants. These catalysts show quite high catalytic activity in the presence of 20 mM of glutathione and even in the whole blood. Furthermore, by conjugating the glycans on the albumin surface as a targeting vector, we successfully carried the artificial metalloenzymes to the cancer regions in mice through “glycan pattern recognition”, and synthesized the anti-cancer drugs for the first time as the true meaning of “catalytically” in mice, to disturb the cancer onset and growth. Our molecular technique is quite powerful; Just a single intravenous injection of the glycosylated artificial metalloenzyme and substrates (starting compounds) led to efficient metal-catalyzed drug synthesis leading to efficient cancer treatment. Since our technology is well targeting, non-invasive, without risk of immunogenicity, non-toxicity, and high efficiency of in vivo drug synthesis, we must point out that our technology could be a possible method to apply to the patients for disease treatment in a hospital, as we indeed have been actively investigating with the companies.