Written by: Our reporter Dai Xiaopei Planning: Chen Yu
Produced by Deep Eye Studio
At present, more than 90% of the medical isotopes produced in my country rely on imports, and there are few types. To change this situation as soon as possible, isotope therapy will create more possibilities.
In order to promote the development of medical isotopes, eight departments including the National Atomic Energy Agency, the Ministry of Science and Technology, and the National Health and Health Commission jointly issued a document proposing that multiple measures should be taken to realize the independent supply of medical isotopes in my country, and gradually solve the passive situation that my country's medical isotopes rely heavily on imports.
Before retiring, Lao Qu studied animals at the zoo.
At the age of 84, he was diagnosed with advanced prostate cancer, which had metastasized to bone.
With the help of his nephew, Lao Qu entered the Department of Nuclear Medicine, Peking University Cancer Hospital.
This was the last straw he wanted desperately to grab.
Most of the patients in this department are cancer patients with a short expected survival like Lao Qu. They have tried various treatments ineffective and have nowhere to go. They came to the emerging nuclear medicine department with the last glimmer of hope.
Old Qu is lucky.
With the help of the radiopharmaceutical radium dichloride-223, which was recently approved in China, his prostate tumor PSA index gradually returned to normal, and his self-care ability was restored.
The "killer" in this radiopharmaceutical is the medical isotope.
"The exploration of isotope application has been in progress, which is a successful case of isotope application. However, at present, more than 90% of medical isotopes produced in my country rely on imports, and there are few types. To change this situation as soon as possible, isotope treatment will create more possibilities. "In February, on a cold and windy night in the north, Liu Chen, deputy chief physician of the Department of Nuclear Medicine at Peking University Cancer Hospital, sighed with emotion.
Achieving the independent supply of medical isotopes is related to the Healthy China strategy.
Previously, in order to promote the development of medical isotopes, eight departments including the National Atomic Energy Agency, the Ministry of Science and Technology, and the National Health and Health Commission jointly issued a document proposing that multiple measures should be taken to realize the independent supply of medical isotopes in my country, and gradually solve the passive situation that my country's medical isotopes rely heavily on imports.
Hundreds of isotopes are used in medicine
Isotopes, invisible, intangible, or smelling, are hidden in everyday life.
For example, americium-241, used in smoke alarms, and carbon-14, used in breath tests to detect Helicobacter pylori, are isotopes.
In theory, different nuclides of the same element with the same number of protons and different numbers of neutrons are isotopes of each other.
There are two types of isotopes - radioisotopes and stable isotopes.
Different from stable isotopes, radioisotopes decay in silence, and various rays generated by their decay can be used to detect or treat tissues in the human body, so as to cure diseases and save lives.
In 1926, Boston physician Lumgart used radioactive radon to study the circulation time between human arterial and venous vascular beds, and was therefore known as the "father of clinical nuclear medicine".
In the 1950s, my country began the exploration of artificial radioisotope production.
In 1958, with the completion of China's first heavy water reactor and the first cyclotron, the Institute of Modern Physics of the Chinese Academy of Sciences (the predecessor of the China Institute of Atomic Energy) started the first batch of radioisotope trial production.
On October 1 of the same year, 33 kinds of radioisotopes were successfully trial-produced, which opened up a new era in the production of artificial radioisotopes in my country, and also accumulated reliable data for the production of isotopes in the future.
Xue Xiaogang, secretary of the Party Committee of the China Academy of Atomic Energy, told reporters that as the earliest unit in my country to develop and produce radioisotopes, the institute has successively developed various types of fission molybdenum-99, fluorine-18, iodine-125, dry iodine-131, etc. Main medical isotopes, as well as a batch of radiopharmaceuticals such as technetium-99m generator, iodine-131 oral liquid, and iodine-125 particle source.
Among them, the fission molybdenum production technology is the most difficult in the preparation of medical isotopes.
In 1998, Miao Zengxing, Institute of Isotope, China Institute of Atomic Energy led a team to conquer the technology of extracting medical fission molybdenum from highly enriched uranium targets, and thus won the first prize of my country's only national scientific and technological progress in the field of isotopes.
Luo Zhifu, the current chairman of the Isotope Branch of the Chinese Nuclear Society and a researcher at the China Institute of Atomic Energy, is one of the key members of the winning team.
In Mianyang, Sichuan, in the early 1980s, the Institute of Nuclear Physics and Chemistry of the Chinese Academy of Engineering Physics (hereinafter referred to as the Second Institute of the Chinese Academy of Physics) started the isotope business.
From 1980 to 1996, the institute successively developed radiopharmaceuticals such as technetium-99m generator, iodine-131 oral liquid, o-iodine-131 hippuric acid and supplied them to the market.
During this period, the second institute of the Chinese Academy of Physical Sciences temporarily interrupted the production of medical isotopes due to relocation, earthquake and other reasons.
In recent years, with the new China Mianyang pile operation at full power and the gradual opening of isotope facilities, the Second Institute of the Chinese Academy of Physical Sciences has successively restored relevant qualifications and production capacity, and achieved large-scale and stable production of iodine-131 oral liquid, taking the lead in building an annual production capacity. Thousand Currie's carrier-free lutetium-177 production line fills the domestic gap.
Yang Zhi, director of the Department of Nuclear Medicine at Peking University Cancer Hospital, said: "In the past, everyone thought that isotopes were radioactive and harmful. Only after exposure did they discover that the benefits of scientific use outweigh the disadvantages, and they can also cure diseases and save lives."
Today, around the world, there are more than 100 radioisotopes used in medicine, of which more than 30 can be used to diagnose and treat diseases.
"Clinically, medical isotopes can be used to treat thyroid cancer, neuroendocrine tumors, prostate cancer, advanced liver cancer and other diseases." Yang Zhi said.
In 2018, Peking University Cancer Hospital carried out a prospective clinical study of PRRT based on lutetium-177.
During the process of recruiting patients, Yu Jiangyuan, one of the project leaders, met Xu Ya, a girl from Fujian.
Xu Ya, a senior in high school at the time, was diagnosed with a pancreatic neuroendocrine tumor, a cancer that once claimed the life of Apple founder Steve Jobs.
After undergoing the surgery to remove the tumor, after weighing, Xu Ya gave up chemotherapy and targeted therapy and entered Yu Jiangyuan's clinical trial group to try PRRT therapy, which has not yet been approved in China.
Four years later, during the treatment period, after graduating from a medical university in Beijing, Xu Ya successfully applied to become a graduate student of the University of Hong Kong.
During the days of living "with tumor", the haze of cancer seems to be gradually dissipating, and she begins to enjoy the beauty of life again.
She loves small animals and life, and occasionally shares lipstick numbers with Yu Jiangyuan.
Yu Jiangyuan was obsessed with Xu Ya, "I look forward to more medical isotopes being used in clinical practice and bringing hope to people".
Import-dependent supply chains face variables
Luo Zhifu, who has been rooted in the nuclear industry for nearly 40 years, clearly remembers two international acquisitions in recent years.
In 2017 and 2018, the Swiss pharmaceutical company Novartis made two international acquisitions, equivalent to spending $6 billion on two radiopharmaceuticals.
Luo Zhifu said that this made the outside world see the application prospects of radiopharmaceuticals and medical isotopes and was shocked.
"The actual demand for medical isotopes in my country will show explosive growth," said Yang Yuchuan, director of the Isotope Research Office of the Second Institute of the Chinese Academy of Sciences. "Molybdenum-99, iodine-131, iodine-125, and lutetium-177 commonly used in nuclear medicine are For example, it is estimated that the annual growth rate will be 5%, 15%, 20%, and 30%, respectively, and the development potential is huge. It is expected that the medical application market of Chinese isotopes will increase to tens of billions in 2022."
Wang Suohui, general manager of China Tongfu Co., Ltd. (hereinafter referred to as China Tongfu), also believes that with the continuous development of society and economy, the public pays more attention to health, people's understanding of radiopharmaceuticals has gradually deepened, and medical isotopes have become "investment depressions".
Stimulated by social demand, the autonomous and stable supply of medical isotopes has attracted much attention.
At this stage, the main means of production of medical isotopes is still by means of reactor irradiation.
At present, there are 5 reactors in my country that have the ability to produce medical isotopes, but due to various factors, they cannot meet the market demand for the time being.
Yang Yuchuan said that at present, only China Institute of Physics II can independently and stably produce iodine-131 and lutetium-177, China Nuclear Power Research and Design Institute has the ability to produce strontium-89 and carbon-14 in small batches, while other reactors have not carried out Mass production of radioisotopes.
"Other nuclides most widely used in clinical diagnosis and treatment, such as molybdenum-99 and iodine-125, all rely on imports." Wang Suohui said.
According to Wang Suohui, there are currently four main medical isotopes imported into China: molybdenum-99/technetium-99, iodine-131, iodine-125, and carbon-14, which are mainly from South Africa, Russia, Belgium, Canada, Australia, etc. nation.
"Because of the high demand, tight time, and the particularity of isotopes, it is almost a race against time for flights transporting medical isotopes to arrive at Beijing Capital International Airport from abroad." Wang Suohui said.
Today, this relatively stable supply chain is also beginning to face variables.
An important reason is that most of the reactors used internationally for radioisotope production will be decommissioned within the next few years.
Currently, almost all of the world's supply of radioactive medical isotopes comes from the following reactors and their corresponding reprocessing facilities: BR-2 in Belgium, HFR in the Netherlands, LVR-15 in the Czech Republic, Maria in Poland, OPAL in Australia reactor, SAFARI-I in South Africa and MURR in the United States.
In addition, there are a small number of RIAR3 and KARPOV piles in Russia and RA-3 piles in Argentina.
"Except for the OPAL reactor, the above reactors have been in service for more than 40 years, facing problems such as aging and poor operating stability, and accidental shutdowns occur frequently. All will be shut down. This will inevitably lead to tight global medical isotope supply. China's medical isotope supply capacity is insufficient, and the market is easily affected." Yang Yuchuan said.
In recent years, the decommissioning of some foreign reactors has led to an increase in the demand for downstream pharmaceutical preparations, and the prices of most medical isotopes have risen.
Liu Chen has a deep understanding of this: "Imported medical isotopes are very expensive. In medical isotope therapy, the cost of isotopes in a single treatment is tens of thousands."
"The burden of rising prices is ultimately passed on to the common people." Luo Zhifu said, "From the perspective of the source, increasing the autonomy of the supply of medical isotopes is more important to meet the people's demand for medical isotopes and keep the money bag for the people. I I think it makes more sense.”
Some medical isotopes have no or limited supply in China, which will affect the treatment of patients.
Previously, Liu Chen treated a patient with advanced prostate cancer who was identified as suitable for treatment with 225Ac-PSMA, a targeted therapy based on the medical isotope actinium-225.
"But at that time, there was no medical isotope actinium-225 in China. India had it, and the price was relatively low. Someone went to India for treatment before, but this patient caught up with the epidemic and had no way to pass." Liu Chen said regretfully.
In October 2019, a proposal led by Academician Zhao Xiangeng, the former vice president of the Chinese Academy of Engineering, with the participation of the Second Institute of the Chinese Academy of Physics, was reported to the State Council, proposing to realize the independent and stable supply of medical isotopes as soon as possible.
Yang Yuchuan said that this proposal is an important thrust for the release of the "Medical Isotope Medium and Long-Term Development Plan (2021-2035)" (hereinafter referred to as the "Plan"), and it will also put on the agenda to reverse my country's dependence on imports of medical isotopes.
The "Plan" proposes that using the unique advantages of medical isotopes for diagnosis and treatment is an indispensable and important means to improve people's health.
This is the first programmatic document for the autonomous development of medical isotopes in my country.
Take multiple measures to improve independent supply capacity
What attracts attention is that the "Plan" proposes to start the construction of 1-2 nuclear reactors for the production of medical isotopes on the basis of improving the capacity of existing research reactors.
"Actually, making good use of any of the existing reactors in my country, or coordinating the operation of existing reactors, can better meet the national demand for medical isotopes. But this involves technical and management issues." Luo Zhifu said , "In the long run, there must be reactors dedicated to the production of isotopes."
Yang Yuchuan emphasized that the construction of nuclear reactors is only one of the means. From the overall point of view, multiple measures are needed to reverse the dependence of medical isotopes on imports.
"It is very important to form the ability to independently supply medical isotopes." Wang Suohui said that the standard for measuring independent supply ability is that domestic medical isotopes can supply the market stably.
"Patients are waiting for use, and the supply of medical isotopes cannot be interrupted. At this stage, we import medical isotopes from abroad, the main reason is the continuous and stable supply abroad."
In this regard, Yang Yuchuan is confident.
He said: "On the one hand, it is necessary to improve the isotope separation capability of the existing reactors as soon as possible. The work of the Second Institute of Chinese Academy of Sciences and the Institute of Nuclear Power in recent years in realizing independent control has proved that this path is feasible, which has given the industry a great deal of attention. confidence."
"On the other hand, clinical demand is very important for the promotion of independent supply capacity." Yang Yuchuan said, "At present, China has not approved the marketing of Lu-177-related drugs, only R&D and hospital clinical trials can be used. However, with the approval of drugs, , the demand will soar in the future, and our company will expand the large-scale supply capacity on the existing basis.”
"At the same time, it is necessary to deploy a new generation of nuclides, that is, alpha nuclides and beta nuclides that integrate diagnosis and treatment." Wang Suohui suggested.
Stimulated and driven by demand, many domestic units and institutions have planned to enter the medical isotope market.
Among the existing entrants, the China Nuclear Power Research and Design Institute proposed to build a solution reactor to produce medical isotopes.
Qinshan Nuclear Power Station, Fujian Xiamen Tsinghua Strait Research Institute, etc. are also eager to try.
China General Nuclear Power Group has also gradually begun to research and design the arrangement of medical isotope production loops on existing commercial reactors to produce much-needed isotopes.
In addition, some large general hospitals are also actively launching cyclotrons to produce medical isotopes such as fluorine-18 in small batches to meet the needs of scientific research and clinical research in hospitals.
In this case, Yang Yuchuan believes that the most important thing to pay attention to is technical capabilities and security issues.
"First of all, the main unit must have both strong technical capabilities, talent teams, nuclear safety management experience and other basic capabilities to ensure the safety of the radiation environment. Second, the project design, construction, and commissioning agencies should be selected with corresponding capabilities and experience. In addition, in terms of resource guarantee, the main unit needs to have a management thinking that safety is overriding, and sometimes it needs to pay a large economic cost and time cost.” Yang Yuchuan said.
Wang Suohui believes that the state should strictly enforce the relevant supervision of medical isotopes.
The industry must follow national regulations, and do not exploit loopholes or edge balls.
The isotope industry has become the new darling of capital, Luo Zhifu is both happy and worried, and even poured cold water on his peers in many conferences.
"The domestic market is so big, and everyone rushing to grab this cake will easily lead to vicious competition. It is still necessary to remain calm."
Luo Zhifu calculated an account.
Taking molybdenum-99 as an example, according to the forecast of an average annual growth rate of 5%, the annual national consumption will be less than 30,000 curies by 2030, and if an existing reactor is operated at full capacity, the annual production of molybdenum-99 will be reduced. can reach 100,000 curies.
"This means that as long as a reactor is built, it must be sold abroad, which involves market competition. The international market does not require molybdenum-99 produced by HEU, which poses a challenge to our production technology."
Of course, for patients, realizing the autonomous supply of medical isotopes is only the beginning.
"The problem of medical isotope supply can be solved sooner or later. In the final analysis, what restricts us is drugs, especially original radiopharmaceuticals." Wang Suohui emphasized.
Luo Zhifu said that although the number and variety of new drugs researched in China are large, most of them are learning and imitation, and they do not have independent intellectual property rights.
In this regard, Yang Yuchuan said that the research on original radiopharmaceuticals in my country is affected by the understanding of new target mechanisms, the development of targeted molecules, and the accessibility of nuclides.
"Innovative development of radiopharmaceuticals should be systematically considered and supported. In the future, it is possible to reverse the passive situation of nuclide supply and drugs by building a comprehensive nuclear medicine platform that tightly couples clinical, R&D, nuclide production, and reactor operation."
In January 2022, China's first nuclear medicine tumor imaging diagnostic class 1 new drug 99mTc-3PRGD2 clinical phase III trial results were released.
This is the result of 20 years of hard work led by Wang Fan, director of the Center for Medical Isotope Research at Peking University, and it is also the epitome of the difficult progress of Chinese radiopharmaceuticals.
Wang Suohui suggested that original research on radiopharmaceuticals should not be stopped, and appropriate cooperation with foreign countries could be done.
Yang Zhi proposed to set up a special research and development of radiopharmaceuticals, formulate corresponding policies for the particularity of radiopharmaceuticals, and allow more exploration in clinical research.
"Medical isotopes are raw materials, and radiopharmaceuticals are weapons and the soul of the development of nuclear medicine."
(Lao Qu and Xu Ya are pseudonyms, our reporter Cao Xiuying also contributed to this report)