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Researchers selected for JST Strategic Basic Research Programs (ACT-X) in the FY2022

Next-gen Treatments that Use Supramolecular Assemblies to Deliver Multiple Drugs Simultaneously and Treat Metastatic Cancer.

I have been studying drug delivery systems (DDS) using supramolecular chemistry. Supramolecular assemblies are constructed by weak interactions such as hydrogen bonds and coordination bonds. These assemblies exhibit properties that individual molecules cannot, and this makes them ideal for use in energy, medicine, and various other fields.

My work involves the development of carriers made of supramolecular assemblies for precise delivery of drugs to specific target cells in the body. The systems work like a capsule; the drug is placed inside or on the surface of the carrier before being administered to the body. It is possible to make a carrier bind to selected cancer cells and releases the drug in response to external stimuli specific to the illness, such as a certain pH level. This means the carrier will reach the targeted cancer cells without damaging the drug it carries and release the drug selectively with a high degree of probability. So far, I have designed and synthesized supramolecular carriers to deliver a variety of protein drugs for use in cancer therapy, regenerative medicine, genome editing, and other applications.

There is already a broad body of similar research, but what makes my work unique is the aim to develop carriers that deliver drugs to the inside of the target cells. Putting protein drugs into cells and using protein function to control cellular function is still challenging, but I believe that it can be done by utilizing supramolecular assembly design affords. If successful, this research will help to generate momentum for the development of drugs for diseases that are currently considered difficult to treat.

Another part of my DDS research involves developing a drug based on supramolecular assemblies for use in boron neutron capture therapy (BNCT), a next-generation cancer therapy. With BNCT, cancer cells are filled with a boron compound and bombarded with neutron radiation, thus destroying the cells.

It has also been suggested that BNCT can potentially eliminate both primary cancer and metastatic cancer. This is called the abscopal effect, which occurs when cancer antigens released from cancer cells destroyed by BNCT activate nearby immune cells, which then travel throughout the body searching for and attacking cancer cells of the same kind. In reality, though, it is tough to induce the abscopal effect reliably due to immunosuppresive microenvironment of tumor tissue. My research arose from a desire to see if it was possible to induce the abscopal effect using carriers made from supramolecular assemblies, and the project¡ªInduction of Abscopal Effect Using Carborane Nano-assembly for Refractory Cancer Treatment¡ªhas been selected for the Japan Science and Technology Agency¡¯s ACT-X Strategic Basic Research Program.

The abscopal effect could be induced by administering a boron agent and a drug (immune checkpoint inhibitor, ¡°ICI¡±) that suppresses the immune braking effect of cancer cells, but delivering both drugs simultaneously to cancer cells and immune cells in the tumor tissue was extremely difficult. I therefore developed a system that used supramolecular assemblies made from boron agents as carriers.

We employed carborane assemblies, which contain boron, as the boron agent. Carborane assemblies are formed by controlling the intermolecular interactions of these molecules, and they can be shaped to suit conditions, such as into spheres, rods, and plates. This is an organic material, too, which means molecules that recognize cancer cells can be attached to its surface. By fine-tuning the form and surface conditions, we should be able to prepare carborane assemblies that can reach cancer cells with a high rate of success, so by attaching ICI to the assembly surface, the carborane assemblies (i.e., the boron agent) and the ICI can be delivered simultaneously the cancer cells. This approach of having another drug piggyback on the boron agent is unique to this research project.

Study using tumor xenograft model mice for metastatic cancer, we have confirmed successful induction of the abscopal effect using carborane assemblies of a certain structure, and complete regression of the cancer in both legs. Moving forward, we plan to study in detail the mechanism through which induced immunity is activated and to determine just how far away from the targeted cells this method remains effective against cancer.

As an engineer, the prospect of developing a DDS tool that¡¯s useful for all sorts of researchers and medical professionals is very motivating. I look forward to working with those researching simulation to uncover the principles behind the design of carriers comprising supramolecular assemblies, and using that as a gateway to more precise carrier design.

Given that the main users of carriers for DDS made from supramolecular assemblies are front-line doctors, I hold regular gather information sessions with multiple doctors as part of my quest to ensure a user-friendly system. Tweaking a system based on users¡¯ feedback is challenging but interesting, and its motivates me to pursue my research. I will strive to keep this personal touch remains a core facet of my endeavors to contribute to the advancement of medical care through my research.