This research aims at developing the technology and system for “Therapeutic In Vivo Synthetic Chemistry”. This therapeutic system could be achieved by the following 4 technological developments. Initially, (1) we establish the library system to rapidly screen the glycosylated albumins to interact with the target cancers. We then (2) prepare the structurally well-defined glycosylated albumins based on the structure-affinity relationship data, and investigate the interaction and internalization properties at the cell-level, as well as pharmacokinetics and toxicity. We further functionalize the glycosylated albumin to perform the drug synthesis in vivo. Thus, (3) in combined use with the genetic engineering techniques, we load the transition metal catalysts onto glycosylated albumin to develop the artificial metalloenzymes to perform the desired synthetic transformations at target diseases. Finally, (4) we perform the metal-catalyzed reactions for drug synthesis, drug release, and drug conjugation, at the cancer regions to efficiently treat them.
Conventional prodrug methods mainly use the tumor-associated enzymes or tumor-specific antibodies, hence their application has been limited, namely, to specific cancer types. On the other hand, the proposed system can be used to synthesize or conjugate the therapeutic molecules at a certain cancer target directly in vivo by applying the optimized glycosylated albumins and various transition metal catalysts to the cancer. Once the metal catalysts are immobilized at the cancer, various synthetic transformations could be performed from the various substrates, so that their therapeutic effects could be directly evaluated in vivo. Alternatively, once the pharmacologically active, but molecules with rather weaker activity, are conjugated on the cancers, then their activities and drug efficacy could be enhanced and prolonged.
As such, our proposed system would significantly expand the applicability of the therapeutic molecules, which have not been recognized as “promising” drug candidates, due to the side effects, instability and/or weak activity. This research proposes the next generation of drug delivery system and drug development strategy from the field of synthetic organic chemistry.
Figure 1: Therapeutic In Vivo Synthetic Chemistry for Cancer Treatment: In this strategy, transition metals will be selectively immobilized at the cancer region by use of the glycosylated albumins through “pattern recognition” mechanism, prior to introducing the starting substances. While large portion are excreted, some of them reach to the target cancer region, and the desired metal catalyzed reactions produce the antitumor compounds, thus treating the cancer without side effects.
Figure 2