Development of radiation countermeasure agents for acute radiation syndromes

Abstract

The risk of internal and external exposure to ionizing radiation (IR) has increased alongside the development and implementation of nuclear technology. Therefore, serious security issues have emerged globally, and there has been an increase in the number of studies focusing on radiological prevention and medical countermeasures. Radioprotective drugs are particularly important components of emergency medical preparedness strategies for the clinical management of IR‐induced injuries. However, a few drugs have been approved to date to treat such injuries, and the related mechanisms are not entirely understood. Thus, the aim of the present review was to provide a brief overview of the World Health Organization's updated list of essential medicines for 2023 for the proper management of national stockpiles and the treatment of radiological emergencies. This review also discusses the types of radiation‐induced health injuries and the related mechanisms, as well as the development of various radioprotective agents, including Chinese herbal medicines, for which significant survival benefits have been demonstrated in animal models of acute radiation syndrome.

Developments of radiation countermeasure agents for the acute radiation syndromes. Exposure to ionizing radiation induced direct or indirect damage effects on molecules, cells, tissues and organs of the body. A number of radiation countermeasure agents that are currently under different status of development and target the core mechanisms of radiation injury, including some Chinese herbal medicines that show the potential to elevate mice radiation survival rate. The WHO updated its list of medicines that should be stockpiled for radiological and nuclear emergencies in 2023.

1. INTRODUCTION

The continuous development and implementation of nuclear technology have led to an increased risk of internal and external exposure to ionizing radiation (IR), resulting in illness and death in exposed populations. IR‐related emergency events can be induced by various factors, including nuclear device‐ and medical‐related accidents, terrorist assaults, military activities, or the use of concealed radiation exposure devices. ¹ It is important to note the current geopolitical risks. For example, four nuclear power plants remain in operation in Ukraine. In an effort to aid in the war effort, the United Kingdom has supplied Ukraine with armor‐piercing rounds containing depleted uranium, further increasing nuclear tension. In addition, with the rapid increase in radiotherapeutic applications, patients and professional workers in clinical settings may experience the effects of overexposure. Therefore, radiological prevention and medical countermeasure strategies are of increasing importance to individuals worldwide.

Nations and the individuals comprising them face serious safety concerns related to radiation preparedness and countermeasures. ² The white paper titled “China's Nuclear Emergency Preparedness” was published in January 2016 to update the country's systemic nuclear emergency preparedness and responses strategies. In March 2022, Russian forces seized control of the nuclear power plant of Zaporizhzhia in southern Ukraine, which was placed under the supervision of the International Atomic Energy Agency in August 2022. On January 27, 2023, the World Health Organization (WHO) revised its list of essential medicines for dealing with nuclear emergencies and the complications induced by radiation exposure, as well as its policy recommendations for the response to exposure events. ³ The aim of the present review was to provide a brief overview of the recent advances in nuclear emergency policies and the development of specific radioprotective agents, including Chinese herbal medicines, that have been demonstrated to exert antiradiation or recovery‐promoting properties in animal models of acute radiation syndrome (ARS) (Figure 1).

FIGURE 1.

Developments of radiation countermeasure agents for acute radiation syndromes. Exposure to ionizing radiation–induced direct or indirect damage effects on molecules, cells, tissues, and organs of the body. A number of radiation countermeasure agents that are currently under different states of development target the core mechanisms of radiation injury, including some Chinese herbal medicines that exhibit the potential to elevate radiation survival rate in mice. The World Health Organization updated its list of medicines that should be stockpiled for radiological and nuclear emergencies in 2023. ARS, acute radiation syndrome; DEARE, delayed effects of acute radiation exposure; EML, Essential Medicines List.

2. RADIATION EXPOSURE AND INJURY

2.1. Sources of radiation exposure

IR includes radiation released from high‐speed protons, neutrons, and electrons, as well as α‐, ß‐, γ‐, and Röentgen rays, and other high‐energy particles that are capable of producing ions on impact with certain biological or nonbiological materials. ⁴ The explosion of nuclear weapons results in the release of various types of energy, each accounting for a different proportion of the total energy content; the heat released accounts for approximately 35%, the blast injury accounts for about 50%, and the radiation released through γ‐rays, X‐rays, and neutrons accounts for about 15% of the total energy released. ⁵ Burns and blunt trauma commonly accompany radiation injuries, resulting in combined injuries, and nuclear power plant accidents can release large quantities of radionuclides. However, the source of radiation exposure often depends on the context. For example, iodine and cesium are the main isotopes of water reactors that are encountered in contaminated areas. In a medical context, overexposure can involve γ‐rays or X‐rays produced from radioactive sources, including ⁶⁰Co, ¹³⁷Cs, or ¹⁹²Ir, or accelerators. In space, sources of radiation include a mixture of γ‐rays, high‐energy protons, and cosmic rays. ⁶

2.2. Radiation‐induced health injury

2.2.1. Acute radiation syndrome

Radiation exposure can occur internally and/or externally through various pathways. For example, whole‐body or localized exposure to radiation at high dose rates of 1 Gray (Gy) or higher most commonly results in ARS. Depending on the radiation dose, the clinical manifestations of ARS include neurovascular subsyndromes (>10 Gy), the gastrointestinal subsyndrome of ARS (>6 Gy), and the hematopoietic subsyndrome of ARS (H‐ARS) (2–6 Gy). The length and intensity of the ARS period depend on the radiation exposure dose, dose rate, and energy; the presence of other clinical syndromes, such as those related to thermal burns and trauma; and other susceptibility factors. ⁷

2.2.2. Delayed effects of acute radiation exposure

The consequences in people who survive ARS or receive sublethal doses of IR are known as delayed effects of acute radiation exposure (DEARE) and mainly result from the late‐onset deterministic and stochastic effects of IR. Common DEARE outcomes include hematopoietic disorders, late hematopoietic injury, pulmonary injury, cataract formation, cognitive deficits, and renal damage. ⁸ , ⁹ , ¹⁰ , ¹¹ , ¹² The incidences of thyroid cancer and leukemia have been shown to increase in children, and there is evidence of sex‐specific differences in the risk and types of cancer caused by such exposure. Some studies have also suggested that these survivors can experience immune senescence and an increased inflammatory response. Fetal exposure can increase the likelihood of microcephaly and short stature later in life, although no increase in the risk of leukemia has been reported. To date, no preventive or treatment measures for DEARE have been approved in clinic.

2.3. Development of radioprotective agents

2.3.1. The mechanisms of action of radioprotective agents

Radiation countermeasures include the use of radioprotective agents that are constantly being developed to counteract the adverse effects of IR exposure. Radioprotective agents are classified based on their mechanism of action: (1) interaction with and chelation of radionuclides; (2) scavenging of free radicals; (3) inhibition of apoptosis; (4) modulation of growth factors and cytokines; (5) expansion of the indications of previously approved drugs; (6) modulation of redox‐sensitive genes; (7) enhancement of DNA repair mechanisms; and (8) therapeutic methods of tissue regeneration, such as stem cell therapy and gene therapy. Among the possible mechanisms of action of radioprotective agents, scavenging of free radicals is the most common. In addition, the U.S. FDA has approved several radiation countermeasures that regulate the expression of redox genes, cytokines, and growth factors have been approved for clinical use. Although stem cell and gene therapies capable of protecting against radiation damage by inducing tissue regeneration remain in development, they could be approved for clinical applications in the future. ¹³

2.3.2. The classification of radioprotective agents

Radiation countermeasure agents are classified by the National Cancer Institute into the following three categories based on the time of administration: (1) radioprotectors, (2) radiation mitigators, and (3) radiotherapeutic agents. Radioprotectors and radioprotective agents prevent damage from IR and should be administered prior to radiation exposure. ¹⁴ Radiation mitigators accelerate recovery from IR damage and should be administered shortly after IR exposure. Radiotherapeutic agents may promote repair or regeneration of tissues in an organism and should be administered after the onset of significant symptoms.

2.3.3. Properties of ideal radioprotective agents

An ideal radioprotective agent would exhibit characteristics that allow it to prevent, protect against, and treat IR‐induced injury. They should also have low toxicity and cost, a rapid onset, long half‐life, and the ability to be orally administered, and should exhibit resistance to IR or high‐temperature environments. Despite significant advances over the past 60 years, the precise mechanisms of radiation injury have not been fully elucidated, and there is still no comprehensive strategy for treating radiation injury. To date, no single radioprotective agent has exhibited each of these properties. ¹⁵

3. WHO ESSENTIAL MEDICINES LIST

The WHO provides recommendations for the composition of national stockpiles for medical countermeasures and radiological emergencies. Table S1 in Supplementary Data summarizes the updated 2023 WHO report on stockpiles for radiation‐ and chemical‐related emergencies.

4. ADVANCEMENT IN THE DEVELOPMENT OF RADIOPROTECTIVE AGENTS

4.1. The mechanism of IR‐induced injury

There are two main mechanisms of IR‐induced injury. The first mechanism involves the direct ionization of target molecules, which damages cellular macromolecules, and the second involves interactions with water molecules to produce free radicals. Because an organism is composed of approximately 75% water, the second mechanism is the predominant means of IR‐induced damage. Most types of low linear energy transfer (LET) radiations (X‐rays and γ‐rays) act on water molecules, producing free radicals that damage macromolecules. ² In addition, IR produces nitrogen species and reactive oxygen species (ROS), which damage intracellular macromolecules. These free radicals cause approximately 70% of the IR‐induced injuries and lead to a constant state of oxidative stress in the organism. ¹⁶ , ¹⁷ , ²⁰ Oxidative damage is the main mechanism underlying the sustained injury induced by IR exposure. ¹⁸ Cellular damage is accompanied by the induction of inflammatory responses, increased immunoreactivity, and the activation of other signaling pathways that ultimately cause apoptosis and other forms of cell death, while accelerating cellular senescence. ¹⁹ , ²⁰ Ultimately, radiation‐induced damage is characterized by oxidative stress and inflammation; therefore, medical countermeasures tend to involve the use of anti‐inflammatory drugs, antioxidants, and free‐radical scavengers. ²

4.2. Development of radiation‐countering agents

Radiation‐countering agents can be classified into different groups depending on their biological and physical properties and their mechanism of action. Studies have focused on the development of such agents for many years, and several articles have reviewed the various agents in the different stages of research and development. ⁴ , ⁵ , ¹⁵ , ²¹ , ²² However, a few radiation‐countering agents have been approved to date for clinical or emergency use.

The four agents of cytokines/growth factors, Nplate (romiplostim), Leukine (sargramostim), Neulasta (PEGylated filgrastim), and Neupogen (filgrastim), have been approved for clinical use for a long time, which are being repurposed as radiomitigators for ARS, or more specifically for H‐ARS. All four agents are included the US stockpile and Neupogen (filgrastim) is in the WHO Essential Medicines Lists. ³ , ²³

Some antioxidants are being investigated as radioprotective agents for ARS. For example, several studies have shown that γ‐tocotrienol (γGT3), a saturated vitamer of vitamin E, exerts protective effects on hematopoietic stem cells and intestinal crypt cells in the gastrointestinal tract in murine and nonhuman primate (NHP) models, accelerating recovery from IR‐induced injury at various doses (5.8, 6.5, 11, or 12 Gy). ²⁴ , ²⁵ , ²⁶ , ²⁷ , ²⁸ , ²⁹ , ³⁰ , ³¹ The radioprotector, indralin (B‐190), was also shown to exhibit radioprotective effects on hematopoietic and other tissues, including the intestines, skin, testes, and salivary glands, and it improved survival rates in monkeys after total‐body irradiation (TBI) at a dose of 6.8 Gy. ³² , ³³ , ³⁴ , ³⁵ , ³⁶ BIO300, a suspension of synthetic genistein nanoparticles, was developed by the Humanetics Corporation to prevent and mitigate the effects of ARS and DEARE, and radioprotective effects have been demonstrated in mice and NHPs. ³⁷ , ³⁸ , ³⁹ , ⁴⁰ , ⁴¹ , ⁴² , ⁴³ , ⁴⁴ AEOL‐10150 is a superoxide dismutase mimetic and metalloporphyrin antioxidant that was shown to be capable of mitigating morbidity and mortality in mice and NHP. ⁴⁵ , ⁴⁶ , ⁴⁷ , ⁴⁸

Cytokines play important roles in the regulation of hematopoietic, immune, and neuronal processes, as well as inflammation and wound recovery. In addition to the aforementioned cytokines, some other cytokines have shown to exert protective effects against IR injury. ⁴⁹ For example, palifermin, a recombinant keratinocyte growth factor (truncated N‐terminal), can prevent or reverse IR‐induced mucositis, ⁵⁰ and radioprotective effects have been demonstrated for several bioengineered erythropoietin analogs, such as darbepoetin alfa, epoetin alfa, Epogen, interleukin‐3, interleukin‐11, and thrombopoietin. ⁵¹ , ⁵² , ⁵³ , ⁵⁴ , ⁵⁵ , ⁵⁶ , ⁵⁷

Medical advancements that have led to reductions in adverse effects after radiotherapy as well as radiation‐induced bystander effects have also aided in the development of mitigation strategies, for example, the activation of tissue repair mechanisms via growth factors and cytokines; prevention of side effects by prebiotics and probiotics; and a reduction in inflammation by bevacizumab, cyclooxygenase inhibitors, angiotensin‐converting enzyme inhibitors, and statins. ⁵⁸ , ⁵⁹ , ⁶⁰ , ⁶¹ , ⁶² Many drugs with antioxidant and anti‐inflammatory effects can prevent DNA damage and reduce the risk of tumor development. For example, melatonin, metformin, curcumin, caffeic acid, and bevacizumab have been shown to exert radioprotective effects and can modulate radiotherapy sensitization. ⁶³ , ⁶⁴ , ⁶⁵ , ⁶⁶ , ⁶⁷

Some agents that have been approved for other indications are being investigated for possible use in the treatment of radiation syndrome; expanding the indications of such agents could lead to an expansion of their clinical use. ⁴⁹ Over the course of more than 20 years, Silverlon antimicrobial dressings have been approved for a diverse range of indications; the primary indications are the treatment of acute dermal wounds and thermal burns (first‐ and second degree), although Silverlon is now being repurposed for the treatment of radiation exposure. ⁶⁸ Similarly, the original indication for Mozobil (AMD3100 or plerixafor) was the treatment of human immunodeficiency virus, and it is now also being used to treat radiation‐induced injury. ⁶⁹ Surfaxin, a synthetic peptide‐containing surfactant used to treat respiratory distress syndrome, and diethylcarbamazine citrate, used to treat filariasis, have been investigated to treat IR‐induced lung injury. ⁷⁰ , ⁷¹ The initial indication for ciprofloxacin was the treatment of gram‐negative bacterial infection, although it has been used to treat combined IR injury. ⁷² Captopril, perindopril, ramipril, and other angiotensin‐converting enzyme inhibitors have been evaluated as radiomitigators in various IR‐related injuries, including those involving damage to the lungs and skin. ⁷³

4.3. Chinese herbal medicines

As an alternative to compounds used in Western medicine, Chinese herbal medicines have been used for thousands of years. Since the 1960s, Chinese researchers have been committed to excavating the treasure house of traditional Chinese medicine resources to identify compounds that could be useful for the development of antiradiation agents. Some Chinese herbal prescriptions and medicines exhibit properties that could prevent against radiation injury with minimal side effects by promoting tissue recovery and inhibiting tissue damage. ²⁰ Chinese herbal prescriptions contain active ingredients capable of preventing free‐radical damage, mitigating DNA damage, decreasing apoptosis, and stimulating repair mechanisms after tissue injury. Many traditional Chinese medicines have been found to significantly decrease the mortality rate of mice exposed to TBI at lethal doses. Some herbs that exhibit antiradiation effects include Angelica sinensis (Oliv.) Diels, Ganoderma lucidum Karst, Panax ginseng, and C. A. Mey. ⁷⁴ Amentoflavones extracted from the traditional Chinese herb Selaginella tamariscina (P. Beauv.) Spring significantly prolonged the mean survival time in C57BL/6 mice after TBI at 7.5 Gy, while attenuating hematopoietic system injury and improving recovery outcomes. In addition, amentoflavone treatment was shown to significantly reduce IR‐induced elevation of ROS levels. ⁷⁵ In another study, treatment with kaempferol, a representative flavonoid, remarkably improved the 30‐day survival rate, decreased ROS levels, reduced apoptosis, and attenuated the morphological changes in C57BL/6 mice that were exposed to TBI with γ‐rays at a dose of 8.5 Gy. ⁷⁶ Administration of emodin, a plant‐derived anthraquinone, was shown to extend the mean survival time and protect against radiation‐induced intestinal injury in mice exposed to TBI at a dose of 9.0 Gy. ⁷⁷ Salvianic acid A is an active ingredient extracted from Salvia miltiorrhiza Bunge, an ancient Chinese medicine used in the treatment of heart and liver diseases; pretreatment with this compound was shown to protect against hematopoietic system injury while promoting the survival rate of Balb/c mice exposed to a 7.5‐Gy dose of ⁶⁰Co γ‐irradiation. ⁷⁸ First discovered as a quinone component of the extracted oil from black cumin (Nigella sativa), thymoquinone was shown to induce apoptosis in pancreatic cancer cells; it also inhibited cancer cell growth in previous studies and improved survival outcomes in mice exposed to various lethal doses of TBI. ⁷⁹

Resveratrol, which was first discovered as a polyphenol component of Veratrum grandiflorum, is used as an anti‐inflammatory and antitumor agent in clinical settings. Mechanistically, resveratrol reduces long‐term radiation‐induced damage to bone marrow cells and intestinal tissue via the upregulation of sirtuin 1 (SIRT1) expression; more specifically, protection against long‐term injury was shown to be mediated through the upregulation of nicotinamide adenine dinucleotide phosphate oxidase 4 and superoxide dismutase 2, and it improved 30‐day survival and attenuated TBI‐induced myelosuppression. ⁸⁰ , ⁸¹

One study showed that the spore powder of G. lucidum could enhance the ability of macrophages and natural killer cells, effectively improving 30‐day survival outcomes and extending the mean survival time in Kunming mice exposed to 7.5‐Gy γ‐irradiation of ⁶⁰Co. ⁸²

Treatment with the extract of Lycium barbarum fruit improved the survival of mice exposed to different doses of irradiation through synergistic effects involving the positive regulation of host metabolism, reconstitution of intestinal flora, potentially increasing populations of beneficial microorganisms, and immunomodulation. ⁸³ The hydroalcoholic extract of the rhizomes of ginger (Zingiber officinale) may improve survivability and attenuate the degree of damage induced by various doses of irradiation by reducing lipid peroxidation and increasing glutathione levels in the liver. ⁸⁴ , ⁸⁵ The radioprotective effects of Ecliptae herba have been demonstrated in a study in which the 30‐day survival rate of mice exposed to 7.2‐Gy TBI was enhanced, and similar effects were observed after treatment with luteolin extracted from the herb. ⁸⁶

Compared with the composition of traditional Chinese herbal extracts, Chinese herbal prescriptions are more complex and may act on multiple targets. ⁸⁷ , ⁸⁸ Many studies have investigated the efficacies of several Chinese herbal prescriptions in protecting against acute irradiation‐induced injuries. Injection of the traditional Chinese medicine Xuebijing (XBJ) has been used clinically for the treatment of severe pneumonia, sepsis, and multiple organ failure resulting from COVID‐19. XBJ contains A. sinensis (Oliv.) Diels, S. miltiorrhiza Bunge, Conioselinum anthriscoides “Chuanxiong,” Paeonia lactiflora Pall., and Carthamus tinctorius L, and studies have demonstrated that its administration can suppress inflammation, reduce apoptosis, and decrease ROS levels in bone marrow cells, thereby attenuating the decrease in survival due to intestinal and bone marrow injury induced by exposure to lethal doses of TBI. ⁸⁹ , ⁹⁰ Another study demonstrated that a formulation composed of Poria cocos (Schw.) Wolf, L. barbarum L, G. lucidum Karst, and Astragalus mongholicus Bunge exerted radioprotective effects by improving the survival of irradiated mice by reducing radiation‐induced injury of the immune system. ⁹¹ Qi tonification and toxin removal induced by Chinese herbal medicines can reduce the recovery time after complete blood cell inhibition and reduce radiation‐induced mortality in mice, ⁹² and Yiqi and Yangyin formulas were shown to improve the survival rate of mice exposed to sublethal doses of TBI by reducing intracellular ROS levels in hematopoietic cells. ⁹³

Collectively, these studies have demonstrated that Chinese herbal medicines exert protective effects against acute radiation injury in various tissues, and their advantages may be related to the reduction in continuous tissue damage caused by radiation exposure and the promotion of subsequent recovery. The identification and modification of active compounds contained in traditional Chinese medicines represent important strategies for the development of antiradiation agents, although further investigation is required.

5. CONCLUSIONS AND PROSPECTS

The threats related to nuclear terrorism and the exposure of first responders, professional workers, and individuals of the general public to radiation during nuclear accidents highlight the need for different radioprotective agents depending on the context. Exposure to radiation may cause ARS, including damage to hematopoietic cells, as well as injury of the gastrointestinal tract and nervous system. To date, a few radioprotective agents have been approved for clinical use; those that are available are mainly for acute hematopoietic radiation injury. There are a few radioprotective agents for other types of ARS, resulting in a failure to meet the requirements of strategic national stockpiles for and the medical management of injuries resulting from IR exposure. Many countries have invested considerable resources to accelerate the development of radioprotective agents; however, many challenges remain.

The future development of radioprotective agents should focus on the following goals. First, studies should focus on the development of novel countermeasure agents and related technologies based on the mechanisms of radiation injury, including screening for candidate compounds or new target molecules. Second, the modification of drugs or preparation of new drug formulations should be evaluated to improve efficacy, reduce adverse effects, increase drug stability, and ensure optimal routes of administration. Third, studies should focus on the expansion of the clinical indications of previously approved drugs to include applications in the protection against radiation. Fourth, researchers should explore radioprotective agents capable of targeting multiple organs, such as the lungs, kidneys, blood vessels, and skin, as well as protection against DEARE. The assessment and characterization of injuries induced by different types of IR should be expanded, as most research to date has involved low LET radiation, such as from γ‐rays or X‐rays. Other types of radiation (especially high‐LET radiation, such as that of protons, neutrons, and heavy ions) should be researched, and protection against them must be investigated, as there are risks related to human space activity and radiation countermeasures. Finally, studies must focus on the development of multiple animal models for each subsyndrome of ARS and DEARE that mimic the mechanisms or pathophysiology of IR‐induced injury in humans to satisfy research and drug evaluation requirements.

AUTHOR CONTRIBUTIONS

Aimin Meng prepared and drafted the manuscript. Bowen Guan, Aimin Meng and Deguan Li searched the relevant literature and revised the manuscript. Bowen Guan and Deguan Li critically reviewed the manuscript.

FUNDING INFORMATION

National Natural Science Foundation of China (grant number: 81972975), Applied Basic Research Key Program of Tianjin (grant number: 22JCZDJC00430), and CAMS Medicine and Health Technology Innovation Project (grant number: 2021‐I2M‐1‐060).

CONFLICT OF INTEREST STATEMENT

The authors declared no conflict of interest. Aimin Meng is an editorial board member of AMEM and a coauthor of this article. To minimize bias, she was excluded from all editorial decision making related to the acceptance of this article for publication.

ETHICS STATEMENT

Not applicable.

Supporting information

Data S1

Guan B, Li D, Meng A. Development of radiation countermeasure agents for acute radiation syndromes. Anim Models Exp Med. 2023;6:329‐336. doi: 10.1002/ame2.12339