Press Release
Creating Smart Nanomachines to Detect Highly Invasive
Cancer After Surgery and Prevent Recurrence– Cancer Metastasis and Recurrence Prevention
Summary:•Matrix metalloproteinases (MMPs) is an enzyme required for cancer cells to metastasize/invade, andcancer cells with higher MMP activity have higher metastasis ability and progress quickly.
In this study, we created polymersomes (smart nanomachines) that act specifically in tissues that
overproduce MMPs, prevent cancer metastasis, and developed a method to remove residual tumor
tissue that could not be visually confirmed after surgery.

•We simultaneously loaded the cell division inhibitor colchicine and the MMP inhibitor marimastat into
MMPs-responsive polymersomes as an enzymatically transformable nanomachine designed toachieve transformation following dePEGylation by cleavage of the inserted substrate peptide byMMPs. The effect on malignant tumors with high MMPs activity was evaluated.

•During transformation, nanomachines with exposed guanidine residues easily penetrate into cells,
and at the same time, by releasing the contained drugs, it exerts an anti-cancer effect.

•Evaluating drug uptake using HT1080 cells derived from human fibrosarcoma that overproduce
MMPs, studying pharmacokinetic and nano-bio interaction using a confocal laser scanningbiomicroscope and evaluating metastasis inhibitory effect using triple-negative breast cancer
transplantation model, the results were published in Advanced Materials (IF = 30.849 in 2021).

J. Li, Z. Ge, K. Toh, X. Liu, A. Dirisala, W. Ke, P. Wen, H. Zhou, Z. Wang, S. Xiao, J. F. R. Van Guyse, T.
A Tockary, J. Xie, D. G.-Carter, H. Kinoh, S. Uchida, Y. Anraku, and K. Kataoka, Advanced Materials,2021.
DOI: 10.1002/adma.202105254
URL: https://onlinelibrary.wiley.com/doi/10.1002/adma.202105254

October 8, 2021, Kawasaki (Japan) and Hefei (China): The Innovation Center of
NanoMedicine, Kawasaki Institute of Industrial Promotion (Director General: Kazunori
KATAOKA, location: Kawasaki-ku, Kawasaki-City; abbreviated name: iCONM), in
collaboration with the Chinese Academy of Science (CAS) Key Laboratory of Soft Matter
Chemistry (USTC: University of Science and Technology), has created nanomachines thatdetect MMPs (matrix metalloproteinases), a principal enzyme for cancer cells to invade
normal tissue, and deliver anticancer drugs according to an announcement in the journal
Advanced Materials (IF = 30.849). As it can target highly invasive cancer cells, it is expected
to inhibit cancer metastasis and recurrence.
Cancer is known as a malignant tumor due to its characteristics of metastasis, recurrence,and invasion, and preventing them is one of the most effective ways for treatment. Whencancer cells metastasize, they need to pass through (invade) normal tissues, and in doing
so, they use extracellular proteases (proteolytic enzymes) called MMPs to destroy thefibrous tissue (matrix) that binds cells to cells and tissues to tissues. In this study, we focusedon tissues and cells that overproduce MMPs and incorporated the cell division inhibitor
colchicine and the MMP inhibitor marimastat into MMPs-responsive polymersomes as an
enzymatically transformable nanomachine (ETN). The ETN was designed to possess anamino acid sequence that serves as a specific cleavage site for MMPs and thus be capableof releasing the PEG and exposing the guanidine residue after cleavage. In the drug uptake
experiment using human fibrosarcoma-derived HT1080 cells, we found that thefluorescently labeled ETN (Cy5-ETN) had a 10-fold higher uptake than that of an inertvehicle without enzymatic transformation behavior. High cellular uptake enabled strong
cytotoxicity of colchicine-loaded ETN with IC50 = 0.015 μM compared to the inert vehicle
with IC50 = 0.402 μM.
Observation of mice treated with ETN using confocal laser scanning biomicroscopy showedno leakage out of blood vessels in the auricle and normal liver; strikingly, the nanomachines
were found to extensively invade the tumor-associated tissues in breast cancer with highMMPs expression.
In pharmacological experiments with mice, we evaluated the antitumor effect for primary andsecondary tumor using MDA-MB-231/LM2 (human) and 4T1 (mice) triple-negative breast
cancer models. As a result, the ETN simultaneously encapsulating with colchicine andmarimastat had a strong antitumor effect and prolonged survival in both triple-negative
breast cancer models. In addition, on the basis of metastasis-prone phenotype of this model
after orthotopic transplantation, the ETN was also confirmed to efficiently inhibit lungmetastasis because of residual tumor targetability. Our results prove an applicabletechnology for not only to cancers but also to other diseases with high expression of MMPs.

Kawasaki Institute of Industrial Promotion (KIIP)
Kawasaki Institute of Industrial Promotion was established in 1988 funded 100% from Kawasaki City forthe purpose of coping with the hollowing out of industry and changes in the demand structure. In order torealize a higher level of market development, transforming R&D type companies, training technologicalcapabilities to support it, human resources development, understanding market needs, etc., by utilizing
the functions of the Kawasaki, KIIP has been contributing to revitalize the local economy by promoting
exchanges of local industry information, advancing technology and corporate exchanges withestablishment of a R&D institutions, developing creative human resources through workshops andpromoting businesses such as expanding sales channels through exhibition business.
https://www.kawasaki-net.ne.jp/
Innovation Center of NanoMedicine (iCONM)
Innovation Center of NanoMedicine (iCONM) started its operation in April 2015 as a core research centerin life science field at King SkyFront on the request of Kawasaki city that KIIP utilized national policies asa business operator and proposer. It is a unique research center that the world has ever seen which isdesigned for the purpose of promoting open innovation through industry-academia-government/medicalengineering collaboration, prepared with state-of-the-art facilities and experimental equipment, thatenables comprehensive research and development from organic synthesis / microfabrication topreclinical testing.

iCONM: https://iconm.kawasaki-net.ne.jp/en/index.html
University of Science and Technology of China (USTC)The University of Science and Technology of China (USTC) is a public research university of China with
scientific and technological research as core strength, under the leadership of the Chinese Academy ofSciences (CAS). Its foundation in 1958 was hailed as "A Major Event in the History of Chinese Educationand Science.". USTC has three National Research Institutions and 6 State Key Laboratories and 18 Key
Laboratories of the CAS. USTC actively promotes cooperation and exchange with around 100 universities
and research institutions in more than 30 nations and regions. In recent years, USTC is ranked in theworld's top 100 universities in the most-widely read university rankings.
USTC: http://en.ustc.edu.cn
October 8, 2021