Self-folding polymers containing gadolinium forming nanosized complexes could be the key to enhanced magnetic resonance imaging and next-generation drug delivery, as demonstrated by scientists at Tokyo Tech. Thanks to their small size, low toxicity, and good tumor accumulation and penetration, these complexes represent a leap forward in contrast agents for cancer diagnosis, as well as neutron capture radiotherapy.

Magnetic resonance imaging (MRI) is a crucial diagnostic tool for cancer, enabling the capturing of detailed images of soft tissues. To visualize tumors more clearly in MRI scans, doctors usually inject patients with contrast agents. These compounds affect the way nearby hydrogen ions respond to the radiofrequency pulses used in MRI. Ideally, contrast agents should selectively accumulate in tumors and increase their contrast in the MRI scan.

However, despite many research efforts, conventional gadolinium (Gd)-chelate contrast agents are reaching their performance limits. Simply put, achieving an optimal dose in the distribution of Gd-chelates within tumors, healthy tissue, and blood has proven challenging without resorting to excessive Gd doses.

Against this backdrop, a collaborative study by a research team from Tokyo Institute of Technology (Tokyo Tech), National Institutes for Quantum Science and Technology (QST) and Innovation Center of Nanomedicine (iCONM), led by Associate Professor Yutaka Miura and Nobuhiro Nishiyama of Tokyo Tech, successfully developed a novel NCA with exceptional performance thanks to an innovative molecular design. Their findings were published in the Advanced Science on November 29^th, 2023.

The proposed nano-contrast agent (NCA) is based around the use of Gd as a contrast agent in what the researchers called a "self-folding macromolecular drug carrier (SMDC)". They incorporated clinically approved Gd-containing chelates into a polymer chain composed of poly(ethylene glycol) methyl ether acrylate (PEGA) and benzyl acrylate (BZA). Since the polymer contained both hydrophilic and hydrophobic segments, it quickly folded itself into a small capsule-like shape when immersed in water, with the hydrophobic segments at the core and the hydrophilic segments at the outer shell.

Using this approach, the researchers could produce SMDC-Gds molecules smaller than 10 nanometers in diameter. Through experiments in mice with colon cancer, they verified that these NCAs not only accumulated better in tumors, but that they were also promptly eliminated from the bloodstream, leading to enhanced MRI performance without toxic effects. "the high accumulation in tumor while quick blood clearance profile of SMDC-Gds allows for the increase in the tumor-to-major organ accumulation ratios as well as minimizing the unnecessary deposition of Gds," explains Prof. Miura.

Moreover, the team also demonstrated a novel effect that puts SMDC-Gds ahead of existing Gd-chelates. Ideally, the motion of Gd ions should be minimal so that their influence on nearby hydrogen ions is steady and prolonged. In the proposed molecular design, the core/shell structure creates a 'crowded' molecular environment that suppresses not only the rotation, but also the segmental and internal motions of Gd ions. The resulting effect is a stronger contrast in MRI images, which will allow for use of alternative elements with safer profiles not only in patients but also environment in future.

It's worth highlighting that the applications of SMDC-Gds extend beyond MRI. These compounds can be used in neutron capture therapy (NCT), a promising targeted radiotherapy technique in which Gds capture neutrons and release high energy radiations, killing nearby cancer cells. Experiments in mice revealed that NCT following repeated SMDC-Gd injection led to greatly suppressed tumor growth. The team believes the reason for this was the selective accumulation and deep penetration of SMDC-Gds into tumor tissues.

Collectively, the researchers' collaborative efforts to achieve these findings underscore the potential of SMDCs not only for better MRI diagnostics, but also as effective tools for treating cancer and other diseases. "This study presents further possibilities for exploiting drug delivery using various therapeutic cargos, and we are currently investigating the development of such SMDC systems," concludes a hopeful Prof. Miura.

Image: Self-foldToing mechanism leads to enhanced contrast in MRI scans
Caption:	By incorporating Gd-based contrast agents into a self-folding polymer, researchers from Tokyo Institute of Technology produced nanosized complexes where the motion of Gd ions is restricted. The small size of these complexes led to better accumulation in tumors, and the limited rotation and motion of Gd ions increased the MRI signal, leading to improved contrast.

Contacts
Emiko Kawaguchi
Public Relations Division
Tokyo Institute of Technology
Email: media@jim.titech.ac.jp
Tel: +81-3-5734-2975

Public Relations Section
Department of Management and Planning, QST
Tel: +81-43-206-3026
Email: info@qst.go.jp

Makoto Shimazaki
Communications Manager
Innovation Center of NanoMedicine
Email: shimazaki-m@kawasaki-net.ne.jp

About Tokyo Institute of Technology
Tokyo Tech stands at the forefront of research and higher education as the leading university for science and technology in Japan. Tokyo Tech researchers excel in fields ranging from materials science to biology, computer science, and physics. Founded in 1881, Tokyo Tech hosts over 10,000 undergraduate and graduate students per year, who develop into scientific leaders and some of the most sought-after engineers in industry. Embodying the Japanese philosophy of "monotsukuri," meaning "technical ingenuity and innovation," the Tokyo Tech community strives to contribute to society through high-impact research.
https://www.titech.ac.jp/english/

About National Institutes for Quantum Science and Technology, Japan
The National Institutes for Quantum Science and Technology (QST) was established in April 2016 to promote quantum science and technology in a comprehensive and integrated manner. The new organization was formed from the merger of the National Institute of Radiological Sciences (NIRS) with certain operations that were previously undertaken by the Japan Atomic Energy Agency (JAEA).

QST's mission is to raise the level of quantum and radiological sciences and technologies through its commitment to research and development into quantum science and technology, the effect of radiation on humans, radiation emergency medicine, and the medical use of radiation.

To ensure that research and development delivers significant academic, social and economic impacts, and to maximize benefits from global innovation, QST is striving to establish world-leading research and development platforms, explore new fields, and serve as a center for radiation protection and radiation emergency medicine.

Website: https://www.qst.go.jp/site/qst-english/

About Innovation Center of NanoMedicine (iCONM)
Innovation Center of NanoMedicie (iCONM) is a leading facility that will serve as the flagship of the cluster for the life science field at the King Sky Front. The facility has been in operation since April 2015 by Kawasaki Institute of Industrial Promotion (KPPI) with a commission of Kawasaki City. Equipped with state-of-the-art facilities and experimental equipment capable of conducting R&D from organic synthesis and microfabrication to preclinical testing in a single step, it is a very unique research facility, unparalleled in the world, designed to promote open innovation through collaboration between industry, academia, government, and medical engineering.
Homepage: https://iconm.kawasaki-net.ne.jp/en/index