Open Chem., 2016; 14: 118–129

Invited Paper Open Access

Matthew Gott*, Jörg Steinbach, Constantin Mamat The Radiochemical and Radiopharmaceutical Applications of

DOI: 10.1515/chem-2016-0011 received February 1, 2016; accepted March 5, 2016. The discovery of radium brought radioactivity to the attention of the general public and inspired many new Abstract: This review focuses on the chemistry and uses of radioactivity. During the first half of the 1900s, application of radium isotopes to environmental radium saw utility in some interesting commercial monitoring, analytical, and medicinal uses. In recent ways including luminescent paint for watch dials [3], years, radium has been used primarily as a tracer to study a spinthariscope for counting alpha scintillations [4], the migration of radioactive substances in environmental radium toothpaste to strengthen teeth [5], radium systems. Tracing the naturally occurring radium isotopes cosmetics [6], and even a radium suppository to “increase in mineral and water sources allows for the determination vitality in men” [7]. One notorious example was Radithor, of source location, residence time, and concentrations. which was marketed as “a cure for the living dead”; the An understanding of the concentration of radionuclides solution was guaranteed to contain 1 µCi (37 kBq) each of in our food and water sources is essential to everyone’s 226Ra and 228Ra [8]. We now know this was just a dangerous health as decay is highly damaging in vivo. gimmick, but the prospect for medical applications was Due to this high radiobiological effectiveness, there is immediately noted for radium. Henri Becquerel received increased interest in using alpha-emitting radionuclides a skin burn from a vial of radium that he carried in his to prepare new, therapeutic radiopharmaceutical drugs. pocket; afterwards Pierre Curie performed experiments Selected studies from the recent literature are provided on his own skin to confirm this effect and reported that as examples of these modern applications of radium radium could have medicinal applications. Early attempts isotopes. at radiation therapy utilized sources of radium salts to treat a variety of ailments including: uterine cervical Keywords: Alpha emitters, Radium, Radiochronology, cancer, arthritis, skin lesions, lupus, and throat cancers Radiotracers, Radiotherapy [9]. Now that we have an increased understanding of alpha radiation and the decay mechanisms of the various radium isotopes, safer practices have been put into place 1 Introduction and radium has been substituted by alternative nuclides for most uses. The purpose of this review is to provide a In December of 1898, Marie and Pierre Curie announced general discussion on some of the modern applications the discovery of a second element found in the uranium- of radium isotopes, including bio- and geochronology, extracted residues of pitchblende ore and, due to the hydrogeochemical analysis, emanation thermal analysis, intense radiation rays it emitted, it was named radium and radiopharmaceutical applications. [1]. Interestingly, radium was independently discovered by Friedrich Giesel shortly after the Curies in early 1899 and he then proceeded to develop an industrial fractional 1.1 Radium and its fundamental chemistry crystallization method to better enable its use [2]. Radium is the heaviest known member of the group 2 elements, the alkaline earth metals. It is only found in very low abundance (approx. 0.1 ppt) as a trace element *Corresponding author: Matthew Gott: Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden in uranium and minerals [10]. Marie and Pierre Rossendorf, 01328 Dresden, Germany, E-mail: [email protected] Curie isolated radium from the residue of pitchblende ore Jörg Steinbach, Constantin Mamat: Institute of Radiopharmaceutical after uranium extraction found in Joachimstal, Bohemia Cancer Research, Helmholtz-Zentrum Dresden Rossendorf, 01328 and it required several tons of the pitchblende residues to Dresden, Germany recover approximately 0.1 gram of radium [11]. It is now

© 2016 Matthew Gott, Jörg Steinbach, Constantin Mamat, published by De Gruyter Open. This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivs 3.0 License. The Radiochemical and Radiopharmaceutical Applications of Radium 119

Table 1: Radium compounds and their basic properties [16-19].

Compound Formula Melting Point (°C) Solubility (g/100 g H2O) Qualitative Solubility

Radium Bromide RaBr2 728 70.6 Soluble in EtOH, dilute acid

Radium RaCO3 - Insoluble Soluble in dilute acid

Radium RaCl2 1000 24.5 Soluble in EtOH, dilute acid

Radium Nitrate Ra(NO3)2 - 13.9 Soluble in weak HNO3 -4 Radium Sulfate RaSO4 - 2.1·10 Soluble in conc. sulfuric acid found in higher yielding sources, including carnotite which have been utilized to isolate radium by fractional sands in Colorado, and uranium ore in both the Republic crystallization. Though the separation is more efficient of Congo-Kinshasa and the Great Bear Lake region of using the bromides, the chloride is more frequently used Canada [12]. Additionally, the possibility of recovering due to material costs. Radium nitrate is also soluble in radium from uranium processing waste has been noted if aqueous conditions, though not as well as the . It the practice was permitted [13]. does become highly insoluble in high acid concentrations

The chemistry of radium is analogous to , (80% HNO3), which is useful to separate radium from which is commonly used as a surrogate due to the intense other elements. Additionally, radium can be isolated by radiation of radium. Radium metal is soft and a lustrous, precipitation as one of its insoluble salts (i.e. radium silver-white color, but it is never found in nature as the sulfate or carbonate). Radium sulfate is highly insoluble pure metal, as it is highly reactive and rapidly reacts with in aqueous conditions and can be used to selectively nitrogen in air to form the black layer of radium nitride, precipitate radium by adding sulfuric acid to a soluble

Ra3N2 [13-16]. Additionally, the metal readily reacts with salt. Most metals will remained dissolved in sulfuric acid, water to produce hydrogen gas and radium hydroxide, but radium sulfate will precipitate once the acid is diluted.

Ra(OH)2, and although the second ionization enthalpy Radium carbonate is insoluble in water, but will readily is nearly double the first (509 and 979 kJ mol-1), it is still dissolve in dilute acids, which can easily separate radium quite low and thus radium is exclusively found in the +2 from water soluble contaminants. oxidation state in aqueous conditions [14,15]. This results from the high lattice energies in the solid salts and the high hydration energies of the Ra2+ [13]. As a result, 1.2 Isotopes of Radium radium exhibits a highly basic character and is difficult to complex. Therefore, most radium compounds are simple There are 34 known isotopes of radium, with mass ionic salts. numbers ranging from 201 to 234 [20]. All of the isotopes Quantitative data on radium compounds is limited are unstable and decay with half-lives ranging from due to its radioactive nature and scarce availability [13-19]. nanoseconds to thousands of years. Only four isotopes Some of the frequently referenced radium salts are of radium are naturally occurring (223/224/226/228Ra) and are listed in Table 1. These salts mostly form white crystals, found as part of the decay chains of primordial 235/238U and but chloride salts that were co-precipitated with barium 232Th [20-22]. chloride have been noted to exhibit a rose tinted color due Radium-226 is a pure alpha emitter produced as part to the barium impurities within the crystal lattice. Though of the 238U decay chain (Fig. 1) and it is the most stable they are fairly stable to radiolysis, the salts degrade and and most abundant isotope of radium. It has a half-life of darken over time as a result of radiation damage and 1600 years, a maximum alpha particle energy of 4.78 MeV, secondary electrons from the alpha decay can interact and a traceable gamma emission at 186.2 keV (3.64 %). with nitrogen in the air causing these salts to luminesce. It decays via a series of nine daughter nuclides emitting The only compounds of radium that are commercially five alpha particles and four beta particles to finally available are radium chloride and . Both become stable 206Pb [20-22]. The long-lived half-life makes the chloride and bromide are highly soluble in aqueous it extremely useful for many environmental applications conditions, but they will precipitate with increased such as radiometric dating, evaluating exchange between concentration of their mineral acids. Both are slightly groundwater and surface water, and determining retention less soluble than their respective barium analogues, times of water sources. 120 Matthew Gott, Jörg Steinbach, Constantin Mamat

two beta particles to finally become stable207 Pb [20-22]. The relatively rapid succession of daughter nuclides decay has led to the use of 223Ra in radiopharmaceutical applications. It is also used in environmental applications as a comparator for 238U composition in source rock and water sources. Radium-228 and radium-224 are produced as part of the 232Th decay chain. Radium-228 is a pure beta emitter with a half-life of 5.75 years and a maximum beta particle energy of 39.5 keV. It decays via a series of three daughter nuclides emitting an alpha particle and two beta particles to become 224Ra. The longer-lived 228Ra finds use in radiometric dating Figure 1: Primary decay chain for primordial 238U. applications. Radium-224 is a pure alpha emitter with a half-life of 3.66 days, maximum alpha energy of 5.69 MeV, and a relatively abundant gamma emission at 241.0 keV (4.10 %). It decays via a series of six daughter nuclides emitting four alpha particles and two beta particles to finally become stable208 Pb [20-22]. Due to its relatively short half-life, 224Ra was used in radiopharmaceutical applications until 2005, but this was stopped due to indiscriminate targeting of healthy tissue. Additionally the relationship with its gaseous daughter, 220Rn, has led to use of 224Ra in emanation thermal analysis. The existence of a long-lived and short-lived radium isotope in the same decay series has enabled the study of radioactive disequilibrium in water sources, sedimentation, and source rocks. Figure 2: Primary decay chain for primordial 235U.

2 Radiochemical Applications

The relative natural abundances, differences in parent and daughter chemistries, and the distinctly varied decay characteristics of the naturally occurring radium isotopes make them useful for evaluating natural phenomena such as volcanic rock formation, groundwater exchange with surface water, continental and coastal water mixing, distribution of nutrients in water sources, and radioactivity accumulation in animals and water sources. As illustrated in Figs. 1-3, the decay of the primordial radionuclides 235/238U and 232Th involves series of radionuclides with varied half-lives and chemical properties [20-22]. In an undisturbed system, all of these Figure 3: Primary decay chain of primordial 232Th. radionuclides are in a state of secular equilibrium, meaning the rate of decay is equivalent for all members Radium-223 is a pure alpha emitter produced as part of the of a given decay chain [23]. However, this equilibrium is 235U decay chain. It has a half-life of 11.43 days, a maximum often disrupted in nature due to the varied reactivity of alpha particle energy of 5.87 MeV, and an abundant the different elements (U, Th, Ac, Ra, Po, and Pb) leading gamma emission at 269.5 keV (13.9 %). It decays via a series to a state of radioactive disequilibrium. This occurs of six daughter nuclides emitting four alpha particles and when a long-lived parent nuclide is removed from the The Radiochemical and Radiopharmaceutical Applications of Radium 121 source leaving the daughter nuclides to decay with their U/Th chronometers including 226Ra/230Th and 210Pb/226Ra characteristic half-lives or a daughter nuclide is removed to evaluate axial and off-axis lava flows for overlapping and begins to grow back in from parent radionuclide decay spread centers on the East Pacific Rise. Examination until the equilibrium is reestablished [24]. Measurement of the various chronometers provided several valuable of this disequilibrium can provide information about the pieces of information. First, all samples taken for time since removal and the chemical fractionation in the this study exhibited 230Th and 226Ra excess suggesting biological or geological source. these formations are quite young (< 8000 a) except for a few dacite samples. Additionally, samples of the axial basalts and basaltic andesite lavas exhibited 210Pb/226Ra 2.1 Using radium chronometers for radiometric disequilibria and therefore had to erupt within the past dating 100 years. The composition of these samples also confirms that the most recent volcanism occurred within the axial There are several radium chronometers that are useful region. Interestingly, some older dacites were found to for radiometric dating but the most commonly evaluated have 226Ra/230Th equilibrium which would place them at relationship for geological processes is between 226Ra > 8000 years old, while some intermediate compositions and its parent 230Th. The determination of time is based were found to be quite younger. It was postulated that on the in-growth of 226Ra after the isolation of230 Th in off-gassing of222 Rn from basaltic magma may have been a source material. The significantly longer-lived230 Th trapped under the more viscous dacite magma creating (7.54 × 104 a) slowly decays into the shorter-lived 226Ra a frothy region. The density imbalance of this region (1600 a) and the disequilibrium of 226Ra/230Th provides may have led to magma mixing and lava of intermediate a measure of time since the isolation of 230Th. In an ideal compositions. This study demonstrates the diverse scenario, the 226Ra/230Th system would be isolated from information possible from radiometric dating. outside 230Th sources and increase solely from 226Ra in- An interesting usage of radiometric dating is the study growth. Once equilibrium is established, the chronometer and age estimation of fish populations, which provides no longer provides an accurate measure of time, but a quantifiable metric to the deep sea fishing industry and can still provide a minimum time since disequilibrium could assist in determining overfishing. Understanding the occurred [25]. The geologically short half-life of 226Ra age of maturity and overall longevity for a given species restricts its usage to samples that are less than 8000 years is necessary for proper management of fisheries. For old, but this still allows for the accurate dating of recent fish, 226Ra is accumulated from the aquatic environment natural events. and, due to its chemical nature, it will deposit into the Several studies have utilized U/Th chronometers crystal lattice as the otoliths form. including 226Ra/230Th to evaluate the age of volcanic rock Otoliths (ear stones) are layered structures of calcium formations [26-28]. The heterogeneity of magma has been carbonate and a gelatinous matrix that form throughout well studied and established [29], which means that a fish’s life. As with the previously mentioned 226Ra/230Th crystals within the magma may be significantly older ratio, 226Ra will decay into the relatively short-lived 210Pb than the eruption event. Plagioclases are silicate-based (22.20 a) and this in-growth can be measured to determine minerals that are a major constituent of the earth’s crust. the age of the fish. Studies of several fish populations have Recently, Eppich et al. [26] demonstrated the existence been published including golden tilefish [30], Antarctic of significantly older plagioclase in two distinct samples toothfish [31], Pacific grenadier [32], orange roughy [33], of dacitic magma from Mount Hood, Oregon, USA from yelloweye rockfish [34], and opakapaka (pink snapper) the Old Maid (approx. 215 a) and Timberline (approx. [35]. Age determinations are based on the disequilibrium 1500 a) eruption events. The average 226Ra/230Th age within first few years of growth by determining the 210Pb estimates showed that the plagioclase crystals within and 226Ra activities in samples are taken from the core the magma were > 4500 a (Timberline) and > 5500 a (Old of otolith for each fish sample. Core samples are used to Maid), which are significantly greater than the eruption keep the method consistent across all age populations. periods. Additionally, the cores of the crystals were shown Additionally, comparisons are made to whole otolith to be > 10000 years old for both populations. Therefore, of juvenile fish of a known age as an external standard. it was demonstrated that these plagioclase crystals must In many cases, radiometric dating was used as a validation reside in the sub-surface for several eruption events until of the traditional age determination using microscopic inclusion by interaction with mafic recharge magma. analysis of the calcium carbonate growth zones. Another recent example given by Waters et al. [27] used 122 Matthew Gott, Jörg Steinbach, Constantin Mamat

For the golden tilefish (26 a), Antarctic toothfish (39 a), from daughter recoil out of the particulate or source and Pacific grenadier (56 a), the traditional age rock. In a system immediately downstream of radium determination method seemed well within agreement precipitation or recently recharged waters, the short-lived with the radiometric dating. However, in some cases, the 224Ra (3.63 d) will reach equilibrium in the water much traditional age determination method is not always valid. quicker than the longer-lived 228Ra (5.75 a), resulting in The opakapaka does not exhibit well-defined annual higher values for the 224Ra/228Ra ratio. Additionally, 223Ra growth zones, which has led to great uncertainty for the and 226Ra decay from two different uranium isotopes (235U­ longevity of this species by traditional age determination and 238U, respectively). From this relationship, it would methods. Previous measurements placed the maximum be expected that the ratio of 223Ra/226Ra would match the observed age at 18 years, but 210Pb/226Ra dating showed 235U/238U ratio (0.046) as the source mineral under steady this species could live significantly longer (45.6 years state conditions. However, similar to the 224Ra/228Ra ratio, mean age of the largest fish). Understanding this critical downstream from a recharge point or Ra precipitation, difference in life span could help ensure sustainable the 223Ra/226Ra will be higher due to the slower in-growth fishing practices since some of these longer-lived fish of 226Ra, providing a marker for water turnover for a given take more time to mature and contribute to repopulation. water source and the disequilibrium from the anticipated 210Pb/226Ra dating is restricted to time’s up to about ratio can be used to calculate the time since water 100 years due to the 22.20 year half-life of 210Pb. As these discharge or radium precipitation. nuclides approach equilibrium and the ratio approaches As water travels into coastal waters from their 1, the method is limited to implying that the ages are continental sources, the shorter-lived 223/224Ra isotopes greater than 100 years. The experimental data for both rapidly decay leaving only the longer-lived 226/228Ra the yelloweye rockfish and orange roughy demonstrated isotopes. Studying the abundance of each radium isotope centurion life spans in several samples. For the orange at various locations within a water source can provide roughy, the longevity has been a source of controversy. insight as to the transport of these isotopes through the The study provided by Andrews et al. demonstrated a water source. This can be used to evaluate and identify long lifespan of 93 year for the older specimens using sources of groundwater exchange with surface water, 210Pb/226Ra dating [33]. This data could help to support discharge of continental waters into coastal waters, previous studies stating the longer life span and invalidate and water retention times [40]. Recently, many studies studies claiming shorter lifespans, which has resulted focused on the introduction of radium isotopes into in overfishing and decimation of the orange roughy coastal water as a marker to better understand the population. Similarly, the establishment of a centurion incorporation of nutrients and freshwater by submarine lifespan for the yelloweye rockfish can influence policy groundwater discharge [41-45]. Sanial et al. [41] used and prevent overfishing of this population. the relationship between 223/224/228Ra to understand the source and timescale of iron and other micronutrient input into the Southern Ocean off the Kerguelen Islands. 2.2 Use of radium isotopes as natural tracers Sampling was performed at various depths and that 228Ra in hydrogeochemistry activity increased with increasing depth, while 223/224Ra activities were high near the seafloor and surface and In addition to the relationship between radium and other below detection limit activities at intermediate depths. members of their decay series, the relative abundance This suggests that vertical mixing only plays a minor of the naturally occurring radium isotopes can also be role in the incorporation of micronutrients in the short- highly variable in geological systems. Several of these term. The high 223/224Ra activity levels at the surface could relationships have been studied in depth. The relationships only be from interaction with shallow sedimentation between the short-lived isotopes 223,224Ra and the long-lived suggesting that horizontal advection plays a major role in 226,228Ra provide information on the age of a distinct water nutrient transport. Additionally, the 224Ra/223Ra ratio was source [36-39]. Since 224Ra and 228Ra are members of the same evaluated at several locations to determine timescale for decay series (Fig. 3), the relative ratio of these isotopes is the dispersion of radium from its origin on the northern not influenced by the parent nuclide concentration in the Kerguelen Plateau and off-shore and found that radium source rock for a system in equilibrium, but by daughter was rapidly transported with a short time of four to eight recoil. Due to the affinity of228 Th for particulate matter, days. In a similar study, Stewart et al. [42] demonstrated 228Ra is usually trapped within or on the surface of the the importance of submarine groundwater discharge for particulate, thus variation of the 224Ra/228Ra ratio results providing nutrients and dissolved into Moreton Bay, The Radiochemical and Radiopharmaceutical Applications of Radium 123

Australia. Surface water and groundwater samples were a state of equilibrium. The activity is measured at room taken from several locations at several depths around the temperature to set a base line for diffusion from the bay to determine the flow of radium and dissolved carbon. coated material, and then it is heated while monitoring the It was found that the short-lived 223/224Ra were found near release of radon. In a system where the material undergoes the shore in four major hotspots, while they were below a physical change, a corresponding change in the release detection limits near the center of the bay. Using the of radon is noted. This measurement allows for materials 223Ra/226Ra chronometer, the residence time of the water to be evaluated for performance under thermally stressful in the bay was determined to be approximately 40 days, conditions/environments. Previous literature used this which is comparable to a previous hydrodynamic model method to examine the permeability of minerals such as value of 50 days. The major source of 226Ra was shown quartz [47] and clay [48]. In both studies, an increased to come from submarine groundwater discharge, which diffusion of radon was noted at lower temperatures due to contributed approximately three times the 226Ra than all of water loss as the crystal dehydrated. Due to the similarity the freshwater sources combined. Dissolved carbon was in size of radon and water (1.34 and 1.40 Å, respectively), estimated to be 20-38 times higher in groundwater sources it was believed the increased diffusion resulted from the than in the surface water sources. The results of this study reorganization of the crystal while losing water. showed the important role of submarine groundwater Recently, Balek et al. [49] have utilized emanation discharge in the nutrient profile of Moreton Bay. thermal analysis to study the diffusion of radon from Another interesting, although complex, relationship anthropogenic analogues of vitrified nuclear waste, for identifying source waters and minerals is between which can provide an understanding of the long-term 226Ra and 228Ra. The abundance of these isotopes in behavior of these materials. To evaluate the potential loss a system is proportional to the 238U and 232Th content in of radioactive materials due to microstructural changes the source rock, but variation occurs due to the mobility of caused by aging and weather, uranium glass produced in uranium and thorium into water sources via erosion and the Czech Republic was tested as an example study. The sedimentation. For example, uranium is highly mobile samples had been buried for 50 years. The glass was used in oxidized water sources and tends to form soluble “as is” for the weathered samples, while other samples carbonate and phosphate complexes, while thorium will had the weathered surfaces laser ablated to pose as “like preferentially bind to particulate or remain in the source new” samples. The study concluded that the two groups mineral. For this reason, samples from carbonate sources behaved similarly at temperatures below 300°C, meaning will have a high 226Ra/228Ra ratio, while silicate sources are that weathering had little effect on the retention of typically closer to 1:1 [24,36,37]. Another factor affecting radionuclides under the conditions expected in a nuclear their presence in a system is the relative rates of daughter waste depository. recoil. With a given alpha particle emission, a daughter nuclide may recoil as much as 100 nm [23]. This significant shift could eject atoms near the surface into the water 3 Radiopharmaceutical Applications source. For a given system, equilibrium will be reached for the relative recoil rates. This recoil equilibrium can be Short-lived, alpha-emitting radionuclides, such as used to identify young water sources, because 228Ra (5.75 a) 223/224Ra, have great potential for use in therapeutic will accumulate much quicker than 226Ra (1600 a). radiopharmaceuticals. Alpha particles are highly energetic (4–9 MeV), relatively large in size, and have a high charge- to-mass ratio, which allows them to readily interact with 2.3 The use of radium in emanation thermal surrounding matter and frequently create ionization analysis events along their path [50,51]. This high frequency of ionization events translates to alpha particles exhibiting a The decay of radium to its inert, gaseous radon daughter high rate of linear energy transfer (LET) of approximately enables the use of emanation thermal analysis. 100 keV µm-1. For this reason, alpha particles are highly Emanation thermal analysis uses radioactive emissions destructive in vivo over a very short range (up to 100 µm). to evaluate the physical changes in material as a function Additionally, the mechanism of action in a cell is more of temperature [46]. A material (i.e. mineral, metal, or destructive than beta particles, gamma rays, or x-rays. glass) is coated with a solution containing 228Th and 224Ra. Alpha particles typically act directly on DNA by inducing The recoil daughters from their decay impregnate the double strand breaks, which destroys the template material with radionulcides, and will eventually reach for DNA replication and repair, making it impossible 124 Matthew Gott, Jörg Steinbach, Constantin Mamat for the cell to recover [52,53]. Due the high LET and of six intravenous injections containing 50 kBq kg-1 effective destructive mechanism, the relative biological doses of 223Ra with four weeks between each injection. effectiveness (RBE) of alpha particles is 20 compared to Patients receiving the treatment with 223Ra exhibited a value of 1 for beta particles, gamma rays, and x-rays. a 3.6-month prolonged survival time over the placebo The effectiveness and small, targeted deposition range group and a 5.8 month improved timeframe before the makes alpha particle therapy an exciting alternative to occurrence of a systematic skeletal-related event (i.e. spinal other radiotherapies. This section of the review focuses compression or pathological fracture) with a reduction of on the clinical application of radium and recent research occurrence of spinal compression [61]. Minimal side effects literature for expanding its use. were noted with this drug and unintended dose to other organs was limited, with distribution studies showing less than 2% of the daughter nuclides migrate away from the 3.1 [223Ra] radium chloride for treatment bone surface [59,60,62]. of metastatic castration resistant prostate cancer 3.2 [224Ra] radium chloride for treatment of Prostate cancer is a frequently occurring disease affecting ankylosing spondylitis about 1 in 7 men worldwide [54-56]. Progression of the disease can lead to an advanced diseased state known as Ankylosing spondylitis (AS) is a systemic inflammatory metastatic castration resistant prostate cancer (mCRPC), rheumatic disease that affects as much as 0.1–1.4% of which is incurable with a median, untreated survival time the world population, with men being three times more of 11.3 months [57]. At this point, treatment is directed likely develop the disease [63]. Additionally, it usually towards attempts to enhance survival and comfort. The presents in mid-twenties, but can affect children as well. primary source of discomfort and pain is associated with This disease is highly debilitating and can cause vertebrae the development of bone metastases. For this reason, in the spine to fuse together, reducing flexibility, and radiotherapeutic treatments have been developed to affecting posture [63]. shrink or eliminate these metastases. Starting in 1948, [224Ra] radium chloride was used to In 2013, [223Ra] radium chloride (Xofigo®; formerly treat AS in Germany [64]. The majority of patients received alpharadin) became the first and only alpha-emitting a series of 10 weekly injections with a cumulative dose radiopharmaceutical to receive FDA and EMEA approval for of approximately 50 MBq. Treatment of AS with 224Ra clinical use, with an intended purpose to treat metastases continued until 1990, and then was re-approved using a associated with mCRPC. A series of six intravenous lower dose of 224Ra from 2000 to 2005 [65-67]; a series of -1 223 injections (50 kBq kg , RaCl2) is administered with each 10 weekly injections was given with a cumulative dose of injection separated by four weeks [58]. Once in the body, about 10 MBq. Good clinical results were reported for AS 223Ra2+ will function as a Ca2+ mimic and complex with the patients, describing a long-lasting benefit with a reduction bone mineral hydroxyapatite at sites of actively growing in the need of anti-inflammatory and analgesic drugs. bone, which occurs at an accelerated rate within metastatic However, long term effect studies reported an increase bone tissue [14,53,58,59]. As mentioned previously, 223Ra in risk of myeloid leukemia for patients treated with 224Ra and its daughters release four alpha particles and two with a particularly high rate of occurrence for patients beta particles before ending at 207Pb (Fig. 2); this delivers a treated while under the age of 21 [68,69]. In the largest large, cumulative dose of (28 MeV) over study, Wick et al. [69] reported epidemiological findings a short range (< 10 cell diameters), damaging the DNA of for a group of 1471 patients treated with 224Ra between 1948 cells within the targeted range, and ultimately killing the and 1975. The follow-ups were performed approximately metastatic cells [53,58,59]. 25 years (median). Causes of death had been determined The effectiveness of Xofigo® was demonstrated for 1006 treated patients and 1072 within a control group. in Phase III clinical trials performed from 2008 to An incident rate of leukemia greater than 1.5 times higher 2011 [53,57,59,60]. 921 patients with confirmed cases was reported for the treated group versus the control group of mCRPC participated in a double-blind randomized (19 compared to 12). A very disproportionate amount of trial with two patients receiving treatment for everyone the cases occurring were myeloid leukemia (11 occurred in the placebo group. The patients received a series with 2.9 expected). The Radiochemical and Radiopharmaceutical Applications of Radium 125

3.3 Radium and targeted alpha therapy

Several reviews have discussed the use of alpha-emitting radionuclides in medicine [70-72]. The current review will specifically focus on the current trends and present use of radium in radiopharmaceutical applications. A growing trend in medical oncology is personalized and targeted medicine. Current research into alpha-emitting radiopharmaceuticals is focused on the development of targeted therapy drugs. The goal of targeted alpha therapy is the incorporation of the radionuclide into a targeting moiety specific to the tumor to increase the efficacy at the target site, while reducing the damage to the surrounding Figure 4: Compounds tested by Henriksen et al. for radium chelation healthy tissues. The urgent need for these specific-binding and stability. moieties was highlighted by the issues with the use of [224Ra] radium chloride; the non-specific attraction of Ra2+ to all actively growing bone is highly problematic and dissociation of radium highlights the difficulty of radium lead to uptake not only at the site of AS, a non-cancerous complexation. Variation of the functional groups could disease, but healthy bone tissues as well. provide a calix complex capable of stabilizing radium As previously discussed, radium is particularly in vivo. Recently, a series of calix crown complexes were difficult to complex due to its electronic structure, which tested by Chen et al. [74] for their ability to retain alkaline has limited its therapeutic application to its simple earth metals. The paper showed that ionizable p-tert- salt, RaCl2. Several studies evaluated the capacity for butylcalix[4]arene-1,2-crown ether ligands exhibited macrocyclic ligands to form stable radium complexes and good Ra2+ selectivity over the lighter alkaline earth metals to attach targeting moieties to radium. Henriksen et al. [73] with moderate-to-high metal loading. The distribution tested 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetracacetic coefficients were determined to be 1000, 120, 3.4, 0.3, and acid (DOTA), diethylenetriaminepentaacetic acid 0.001 for Ra2+, Ba2+, Sr2+, Ca2+, and Mg2+, respectively. The (DTPA), 4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo[8.8.8] kinetic stability of these complexes was also evaluated hexacosane (Kryptofix 2.2.2), and 5,11,17,23-tert-butyl-­ following a similar method as used by Henriksen et al. 25,26,27,28-tetrakis[(carboxy)methoxy]calix[4]arene and < 5% of the 223Ra had been extracted after 24 hours. (calix[4]arene tetraacetic acid). These chelators are These ionizable calixarene-crown ethers could be used to illustrated in Fig. 4. Competition extraction experiments complex 223Ra and link it to a targeting moiety. In a recent were performed for the hydrophilic DOTA, DTPA, and study, Boston et al. [75] suggested that the replacement of Kryptofix 2.2.2 versus the lipophilic calix[4]arene the p-tert-butyl­ functional groups with hydrogen could tetraacetic acid complex to determine relative extraction lead to a higher degree of selectivity. Modification of these coefficients. The cyclic chelator, DOTA, was shown to calix crown complexes could possibly provide a stable provide a higher extraction coefficient than the open chelate for radium. chain, DTPA. This finding is consistent with previous In general, an additional challenge using alpha- literature, which established that the fixed cavity size of emitters is that the intense energy of the daughter recoil cyclic chelators are more size exclusive and exhibit higher has more than sufficient energy to destroy any chemical selectivity compared to their open chain equivalents. bond, which would allow the daughter nuclides to migrate The larger macrocycles, Kryptofix 2.2.2 and calix[4]arene from the tumor site and damage healthy tissues [76]. tetraacetic acid, provided more stable complexes. The Recently, interesting research has been performed by calix complex performed the best overall, though the several groups to encase radium in a stabilizing vesicle stability under biological conditions was still insufficient such as a nanoparticle or liposome to prevent the release for in vivo use. The kinetic stability of 223Ra-containing of daughter nuclides and depositing all radiation at the calix[4]arene tetraacetic acid was evaluated by mixing the target site. Piotrowska et al. [77] used functionalized calix-containing organic phase with an aqueous phase nanozeolites to encapsulate 224/225Ra for use in targeted containing serum abundant metals (Na+, K+, Mg2+, Ca2+, alpha therapy. Zeolites are aluminosilicate nanoparticles and Zn2+) . After 10 minutes, it was found that 35% of the build up of tetrahedral structures with channels and cages radium had dissociated into the aqueous phase, this large capable of incorporating radium (Fig. 5). They reported 126 Matthew Gott, Jörg Steinbach, Constantin Mamat

Figure 5: Functionalized nanozeolite by Piotrowska et al. for radium encapsulation.

alpha particle emissions from the daughters destroy the local tumor, which then provides a large supply of tumor antigens that trigger an immune response. Triggering this immune response was demonstrated in mice recently (Confino et al.) [75] to reduce the recurrence of a tumor by re-inoculation with the same tumor cells. 77% of the population did not redevelop tumors after DaRT compared Figure 6: Ca-ionophore A23187 utilized to transport radium into to 33% for the control group. Additionally, a significant liposomes. increase in the survival rate was noted for DaRT treated mice (63% for treated vs. 29% untreated). Additional a successful production rate with greater than 99.9% of studies have shown the prospect of this therapy for 224/225Ra incorporated into the nanozeolite (30–70 nm) and treating squamous cell carcinomas [81], glioblastomas [81], effective daughter retention with less than 0.5% leakage melanoma [81], breast [80], colon [80,81,85], pancreatic observed. As noted by de Krujiff et al. [70], it was not [84], prostate [81], and lung cancers [83]. This method does mentioned if equilibrium had been reached in solution for have its drawbacks though. Due to its long half-life, 212Pb these studies. Out of an equilibrium state, it is possible that was observed to migrate away from the tumor resulting in the stability and distribution might be drastically altered. a higher dose to several organs, most notably the kidneys Liposomes have been investigated by Henriksen and liver [82]. The amount of radionuclide escaped was et al. to encapsulate and take 223Ra to a tumor site [78]. relative to the size of the tumor; 90% 212Pb leakage in They utilized Ca-ionophore A23187 (Fig. 6) to load a 0.1 g tumor, but only 12% in a 2.4 g tumor. Thus again, radium into preformed PEG-liposomes, which were then highlighting the necessity of stabilizing radium and its functionalized with folate-F(ab’)2-antibody fragments decay daughters to minimize dose to healthy tissues. as a targeting moiety. A high radium loading yield was achieved and stability was demonstrated using serum studies. Jonasdottir et al. [79] transitioned the use of 4 Summary liposome-encapsulated radium into in vivo studies using a mouse model. As before, the radium was incorporated Radium has found utility in many applications since it was into PEGylated liposomal doxorubicin using ionophore isolated by the Curies in 1898. Today, it is an important mediated loading. Biodistribution studies demonstrated source for the determination of nutrient and water flow in not only a migration of daughter 211Pb and 211Bi, but free environmental systems. Additionally, it has been utilized 223Ra was shown to accumulate on bone surfaces of the in the radiometric dating of volcanic rock, minerals, and skull and femur. It was postulated that the liposomal even fish. Since its discovery, radium has been used in 223 223 Ra was cleared from the blood and then metabolized by medicinal applications and now RaCl2 has become the macrophages in the reticuloendothelial system. first alpha-emitting radionuclide to receive FDA and EMEA With the difficulty of mitigating migration of the approval for clinical use. With the growth of targeted daughter nuclides, Cooks et al. [80-85] actually decided alpha therapy, radium will continue to find application to use the dispersion of the daughter nuclides to their for the treatment of various diseases. The current research advantage. Diffusing alpha-emitters radiation therapy focus in development of these drugs, not only for Ra but (DaRT) implants 224Ra-loaded wire in or near the tumor. all alpha emitters, is the producing stable chelate systems Recoil from alpha decay ejects the decay daughters into to keep the radium and its daughters localized at the target the tumor, while the 224Ra remains immobilized in the wire. site. This review has been provided as a brief overview of This method ensures the 224Ra remains at the tumor site. The the modern uses of radium. The Radiochemical and Radiopharmaceutical Applications of Radium 127

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