Biomimetic mineralization: the birth of ultra-high relaxation magnetic resonance contrast agents

Magnetic resonance scanning technology is a widely used imaging diagnostic method in clinical practice, and plays an indispensable role in the diagnosis and evaluation of various diseases such as neurological diseases, cardiovascular and cerebrovascular diseases and tumors. Contrast media can further enhance the effect of magnetic resonance imaging and “escort” the accurate diagnosis and treatment of diseases.

A few days ago, the team of academician Yu Shuhong of the University of Science and Technology of China, together with the team of Professor Lu Yang of Hefei University of Technology and the research team of the University of Konstanz, developed a new type of ultra-high relaxation rate magnetic resonance contrast agent. The research results were recently published in Nature Communications.

“Compared with the contrast medium currently in clinical use, the new contrast agent can image the details of fine small blood vessels and tissues more clearly at a lower dose, which is conducive to clinical diagnosis.” Dong Liang, co-first author of the paper and a distinguished associate researcher at the Hefei National Research Center for Microscale Material Science (now a distinguished researcher at the Hangzhou Institute of Basic Medicine and Oncology, Chinese Academy of Sciences), introduced to China Science News.


Xu Yunjun (left), co-first author of the paper and chief physician of the Department of Imaging, The First Affiliated Hospital of the University of Science and Technology of China, and Dong Liang, co-first author of the paper and distinguished associate researcher of the Hefei National Research Center for Microscale Material Science (right).

Whimsical idea: Biomimetic mineralization brings new ideas

“Contrast agents, also known as ‘contrast agents’, are mainly used in clinical CT, magnetic resonance imaging and ultrasound and other enhanced examinations to ‘develop’ blood vessels or parts with vascular blood supply, so that it is easier to find lesions in clinical practice.” Xu Yunjun, co-first author of the paper and chief physician of the Department of Imaging, The First Affiliated Hospital of China University of Science and Technology, said, “Generally speaking, the higher the relaxation rate, the more significant the contrast enhancement effect of the MRI contrast medium. ” 

At present, the contrast medium used in clinical practice are all Gd (chemical element gadolinium)-based small molecule drugs, but the relaxation performance is limited, and there is also a hidden danger of gadolinium ion leakage; In recent years, the gadolinium-based nanocrystals developed and synthesized by researchers have shown good application prospects, but their crystallinity often limits the ability of gadolinium ions to coordinate with water, and the relaxation rate of materials is also limited by this. At the same time, the preparation of materials often requires high temperature and high pressure, the synthesis process conditions are harsh, it is difficult to scale up the preparation, and the industrial production transformation is limited.

Since the ability of gadolinium ions to coordinate with water affects the relaxation performance of gadolinium-based contrast media. If the water content of the gadolinium-based nanomaterial itself is directly increased, can the interaction between gadolinium ions and water molecules be enhanced, the utilization rate of gadolinium ions can be increased, and the relaxation performance can be improved. Dong Liang and they made a bold guess.

“But this new plan is not easy to achieve.” Dong Liang explained that the preparation process of nanomaterials often goes through high temperature, centrifugation and other steps, there is dehydration, crystallization and other phenomena, and the final product cannot retain too much water.

In nature, amorphous calcium carbonate is widely present and has high aqueous properties. Inspired by this, the team prepared a stable high-aqueous material – gadolinium-doped amorphous calcium carbonate – with the help of biomimetic mineralization strategy at room temperature and pressure.

“I didn’t expect our whim to become a reality.” Dong Liang confessed that at the beginning, they were also puzzled, can such a simple synthesis method achieve high requirements for materials? However, after experiments, the results are positive, and directly increasing the water content of gadolinium-based nanomaterials can bring gains to their relaxation performance. Dong Liang suggested that the development of chemical materials science needs to be based on continuous attempts.

8 years of perseverance: only to better meet clinical needs

In fact, the study lasted 8 years from the beginning of the project design to the final publication of the paper. Dong Liang said, “Because our original intention and goal is to hope that the research results can move from the laboratory to the clinic.” ” 

When they really do it step by step, they find that the problems to be solved are coming from all directions. One of the difficulties is to evaluate the multiple safety, in vivo stability, drug metabolism, and possible toxic side effects of the material according to clinical needs.

“Over a considerable period of time, we have repeatedly tested and validated the preparation process, material characterization, performance influencing factors, the exact relationship between water content and relaxation rate, and a wide variety of cell and animal evaluations.” Dong Liang said that each data will be confirmed by several or dozens of measurements, and these will take a long time.

“It’s common for tests to be done at night, and sometimes people will discuss the results while testing, and even find out at dawn, but everyone has no complaints.” Xu Yunjun recalled.

They did not rush to exchange some data or incomplete scientific arguments for the publication of papers, but jointly sunk down to solve the problem and sort out the mechanism. Dong Liang said, “It is a blessing in scientific research to meet like-minded partners who are willing to do solid research together. ”

Improved upgrades: There are more issues to be addressed for a successful phase

The final study proved that the relaxation rate of this new nanocontrast medium is about 12 times that of the current clinical contrast medium (gadolinopentetate meglumine injection).

At the same time, the researchers used clinical instruments and equipment to image and compare a variety of experimental animals such as rats and New Zealand rabbits. The results show that the new nanocontrast media shows clearer and better contrast enhancement at lower doses.

“The design and imaging of the new contrast agent are excellent, the data are convincing, and the magnetic resonance imaging capabilities of the contrast agent in vitro and in vivo are well demonstrated. This work provides new insights into the design of magnetic resonance contrast agents with clinical translational potential. A reviewer said.

So, when will this new nanocontrast agent really go to the clinic for the benefit of patients?

Dong Liang believes that material production is the first hurdle. “When we built the material system, we imagined that if the contrast medium could reach the conversion level, then its production could not become a bottleneck for its transformation.”

Therefore, when designing the preparation route, they took the scale-up production process, macrosynthesis stability, preparation cost, etc. as important considerations, and solved these problems one by one.

Dong Liang introduced that at present, under normal temperature and pressure conditions, several liters of materials can be produced in a few minutes, which provides a guarantee for its clinical application transformation.

“But it will take a long time for professional pre-clinical evaluation to really be used in the clinic.” Xu Yunjun said that in the completed preliminary evaluation, it was found that the material still encounters liver enrichment problems like most nanomaterials in the metabolic process. This difficulty will also be an important factor in whether the new nanocontrast agent can truly benefit patients in the end.

Dong Liang said, “Next, the team will further optimize the performance of materials, improve and upgrade on the existing basis, and strive to let the second and third generation products enter the clinical trial stage.” (Source: Wang Min, China Science Daily)

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