Toward multitasking drug carriers that do more than just deliver

When we take medicines orally or via injection, it spreads throughout the body before resulting in the intended effect. While these methods are effective, they can cause harm to healthy cells by exposing them to the drug. This is where drug delivery systems (DDSs) comprising nanoparticles, hydrogels, micelles, and liposomes come in. Simply put, DDSs work by encapsulating the drug and carrying it toward the target location, improving drug availability at the target site and minimizing off-target drug distribution and side effects.

DDSs are often designed using biopolymers sourced from biologically compatible materials, such as proteins, polysaccharides, etc. owing to their biodegradability and functional versatility. Moreover, a nanoparticle-based DDS – which uses particles with sizes about one-thousandth the width of a human hair – provides enhanced functionality because of its increased surface area. This combination of nanoscience and biopolymers has paved the way for “nanomedicines.”

Nanomedicine lies at the intersection of materials science, biology, and drug development. Nanomedicines have garnered much attention as anti-inflammatory agents, tissue-repair drugs, and anticancer drugs. However, owing to their low drug-loading capacity, increased dosage or frequent administration is often necessary to achieve the desired therapeutic effect.

Professor Kurisawa Motoichi’s research at Japan Advanced Institute of Science and Technology (JAIST) addresses this challenge by using an integrated approach combining the principles of biology, polymer chemistry, materials science, pharmacology, and biomedical engineering.

How the humble green tea found its way into nanomedicine

Prof. Kurisawa – a JAIST alumnus since 1998 – earned his PhD in Materials Science before going on to pursue postdoctoral research at Tokyo Women’s Medical University and Kyoto University. Following this, he joined the Agency for Science, Technology and Research (A* STAR), Singapore, where he worked as a Principal Investigator (PI) for 18 years before moving back to JAIST as a Professor in 2021.

“During my PhD days, I was trained in the principles and techniques of Materials Science. But it is during my postdoctoral research in a medical school that I started understanding the translational value of my research. This motivated me to pursue research at the interface of materials science and pharmacology to build unique materials for targeted drug action,” says Prof. Kurisawa as he recounts his research journey.

As a PI at A*STAR, Prof. Kurisawa extensively focused on biomedical engineering research, translational drug delivery, and regenerative medicine, which shaped the interdisciplinary foundation of his current research at JAIST. While his original research proposal at A*STAR had been on hydrogels – a water-soluble polymer-based DDS – he kept a back-up proposal based on a different DDS handy. Remarkably, it was this back-up proposal that eventually turned out to be a successful project, resulting in several landmark publications. The idea of this proposal was simple – using a nanoparticle carrier with intrinsic therapeutic effects to synergistically improve drug efficacy, addressing the problem of low drug-carrier ratio.

To this end, Prof. Kurisawa’s team used green tea catechin molecules to design such nanocarriers. Epigallocatechin gallate (EGCG) – a major ingredient of green tea – is known to have antioxidant, anti-angiogenic, and anticancer effects. By developing EGCG nanoparticles, the team designed a DDS that not only served as a drug carrier but also as a therapeutic agent. This formed the basis of Prof. Kurisawa’s 2014 publication in Nature Nanotechnology based on a study where his team demonstrated self-assembly of EGCG molecules with the anticancer protein Herceptin, forming stable micellar nanocomplexes with greater anticancer effects, both in vitro and in vivo and lower accumulation in other organs.

The “Sen Tan” edge (cutting-edge) of drug delivery research

Prof. Kurisawa’s research on dual-functioning EGCG-based nanoparticles enabled a solid foundation toward validating this approach for multiple therapeutic functions. His research on designing highly stable micellar nanocomplexes (MNCs) with high drug-loading capacity, based on the self-assembly of the anticancer drug doxorubicin (DOX) with poly(ethylene glycol)–epigallocatechin-3-O-gallate (EGCG), is an example of this. With an exceptional drug-loading capacity of 88%, these DOX-loaded MNCs showed significant tumor inhibition in vivo compared to free DOX and liposomal DOX.

Similarly, Sunitinib-loaded MNCs were deployed against renal cancers, which exhibited enhanced anticancer effects compared to free Sunitinib. This demonstrated better tumor-targeting, anti-angiogenesis, and apoptosis induction, with reduced toxicity towards healthy cells.

More recently, in 2022, Prof. Kurisawa’s team demonstrated bone marrow-targeted delivery of anti-acute myeloid leukemia (AML) drug using green tea catechin-based MNC. With poor access to bone marrow, current anti-leukemia drugs have limited clinical success in treating AML. By contrast, the green tea catechin-based MNC was found to synergistically amplify the anti-leukemic ability of sorafenib. In vivo experiments demonstrated a near 11-fold greater bone marrow accumulation of the nanocomplex compared to free sorafenib. This technique was adapted to resolve chemoresistance in multidrug-resistant leukemia models. The nanocomplex promoted better accumulation of sorafenib within leukemia cells, increasing their chemosensitivity.

Additionally, the Kurisawa team developed injectable hydrogel systems that safely assemble inside the body to perform specific functions. Along with his long-term collaborator, Professor Emeritus Dr. Myron Spector from Harvard University, Prof. Kurisawa designed hydrogels for treating stroke, a condition with very few treatment options. Using animal models, they demonstrated that these hydrogels released neuroactive substances that attracted neural stem cells to the lesion site, promoting tissue repair and regeneration. Since then, Dr. Spector and Prof. Kurisawa have co-founded three start-ups in Boston where they are currently developing injectable hydrogels for treating eye diseases in humans.

Prof. Kurisawa reflects on the “Sen Tan” (cutting-edge) aspect of his research: “Drug design has rapidly evolved, with new drugs being reported frequently. As researchers working on drug carriers, it is crucial to remain relevant and keep up with the dynamic landscape of drug design. I believe that our research has been able to achieve this.”

Research at JAIST

A vibrant and supportive academic ecosystem is key to a successful research career. From setting up his laboratory, providing access to state-of-the-art infrastructure, enabling collaboration across disciplines, to promoting entrepreneurial initiatives, JAIST has generously supported Prof. Kurisawa’s academic goals. Furthermore, this ecosystem benefits students as well. From design preparation to efficacy evaluation in animal models, all facilities are provided in-house.

Additionally, programs such as Japan’s Peak Research Initiatives (J-PEAKS) help researchers initiate collaborations with clinicians from Kanazawa University, which is essential for translating research into clinical practice. Such programs are also able to orient students toward understanding the societal commitments of their academic disciplines.

Developing a “habit” of meaningful research

With experiences ranging from being a theory-focused PhD student to a researcher aware of the societal impact of DDSs, Prof. Kurisawa offers valuable guidance to aspiring researchers.

“I was not an exemplary research student and often got scolded by my professors! But I focused on improving my skills every day, which led to small improvements that compounded to more meaningful successes eventually. Making a habit of developing yourself gradually is more practical than expecting overnight changes in your skills,” he reflects.

Prof. Kurisawa advises young researchers to be mindful of the broad societal implications of their work instead of being solely focused on developing methodological skills. A meaningful academic career stems from a right balance of strong research skills and a clear understanding of the societal impact of one’s work.

For budding scientists, keeping up with global research is essential to stay abreast of the rapidly evolving developments in your field. While timely communication of results is important, Prof. Kurisawa cautions that rushing through objectives to complete one’s thesis can make the research journey less fulfilling.

Looking at his own academic journey through the lens of his favorite movie, Top Gun: Maverick, Prof. Kurisawa remarks: “I first watched the original ‘Top Gun’ about 30 years ago. After returning from Singapore, I watched its sequel, and it moved me deeply. It reminded me of my own journey over the last 30 years. Just as the fictional world of the movie had evolved, I had survived multiple ups and downs in my academic career that had transformed my outlook toward research. In that moment, I felt a deep appreciation for my career and gratitude for the path I had chosen—and for the fact that I'm still here, pursuing the research I have always been passionate about.”

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About Japan Advanced Institute of Science and Technology, Japan

Founded in 1990 in Ishikawa prefecture, the Japan Advanced Institute of Science and Technology (JAIST) was the first independent national graduate university that has its own campus in Japan to carry out research-based graduate education in advanced science and technology. The term “Advanced” in JAIST’s name reflects the Japanese term “Sen Tan,” meaning “cutting-edge,” representing the university’s focus on being at the forefront of innovative research and education. Now, after 30 years of steady progress, JAIST has become one of Japan’s top-ranking universities. JAIST aims to foster capable leaders through its advanced education and research curricula. About 40% of JAIST’s alumni are international students. The university has a unique style of graduate education to ensure that students have a thorough foundation to build cutting-edge research and technology in the future. JAIST also works closely with both local and overseas academic and industrial communities, promoting industry–academia collaborative research.

Website: https://www.jaist.ac.jp/english/