Selection of radionuclide(s) for targeted alpha therapy based on their nuclear decay properties

Abstract

Targeted alpha therapy (TAT) is a promising form of oncology treatment utilising alpha-emitting radionuclides that can specifically accumulate at disease sites. The high energy and high linear energy transfer associated with alpha emissions causes localised damage at target sites whilst minimising that to surrounding healthy tissue. The lack of appropriate radionuclides has inhibited research in TAT. The identification of appropriate radionuclides should be primarily a function of the radionuclide’s nuclear decay properties, and not their biochemistry or economic factors since these last two factors can change; however, the nuclear decay properties are fixed to that nuclide. This study has defined and applied a criterion based on nuclear decay properties useful for TAT. This down-selection exercise concluded that the most appropriate radionuclides are: ¹⁴⁹Tb, ²¹¹At/²¹¹Po, ²¹²Pb/²¹²Bi/²¹²Po, ²¹³Bi/²¹³Po, ²²⁴Ra, ²²⁵Ra/²²⁵Ac/²²¹Fr, ²²⁶Ac/²²⁶Th, ²²⁷Th/²²³Ra/²¹⁹Rn, ²²⁹U, ²³⁰U/²²⁶Th, and ²⁵³Fm, the majority of which have previously been considered for TAT. ²²⁹U and ²⁵³Fm have been newly identified and could become new radionuclides of interest for TAT, depending on their decay chain progeny.

Introduction

Targeted alpha therapy (TAT) is a form of molecular radiotherapy utilising alpha-emitting radionuclides that specifically accumulate in disease sites. Typically, either (1) the radionuclide has inherent targeting properties due to its natural bio-distribution, for example, ²²³Ra is a calcium mimic and thus, like calcium, naturally accumulates in areas of bone that are undergoing increased turnover, such as where bone metastases are forming, or (2) the alpha-emitting radionuclide is attached to a moiety (such as a peptide or an antibody) that targets a specific receptor or transporter, overexpressed in disease. Consequently, the radiopharmaceutical accumulates in cancer cells with this feature. The alpha emissions from these radiopharmaceuticals have a high linear energy transfer (LET) depositing a large dose of ionising energy over a short distance, and so are damaging to the cells in which they accumulate. The radionuclides deliver a high radiation dose causing double-strand DNA breaks, leading to cell death and providing a therapeutic effect. TAT is employed for the treatment of metastatic disease, as the radiopharmaceutical can be delivered systemically by intravenous infusion, and accumulates, and deposits the radiation dose in the disparate metastatic sites.

A number of factors determine which alpha-emitting radionuclides are exploitable for TAT research:

1. nuclear decay properties,

2. sources and production methods,

3. cost and availability,

4. biochemistry and radiobiology.

Of these, it is only the nuclear decay properties that are immutable. The other factors could be influenced by developments in technology or investment in the supply chain. Currently, TAT is restricted, in both terms of research and therapeutic use, predominantly by the availability of alpha-emitting radionuclides [1]. Researchers can only work with the radionuclides to which they have access, and therapeutic use is restricted to the limited sources of clinical-grade material available. Therefore, researchers may not be working with the radionuclide with the most appropriate properties.

This paper details the nuclear decay properties that a radionuclide should possess to be appropriate for use in TAT and provides a method for the selection of such radionuclides.

Nuclear emission properties criteria

For a radionuclide to be appropriate for TAT, it should ideally possess the following properties:

• (1)The radionuclide must decay with alpha particle emission or be a part of a decay chain that contains an alpha particle emitter.

The effectiveness of TAT relies on the properties of alpha particles. It is the release of these alpha particles that provide the lethal radiation payload to cells. The radiation energy deposited into the matter is measured by LET, the mean rate of energy loss of a particle per unit length of its path length. Alpha decay has the highest LET of any radioactive decay with high energy (5–9 MeV) [2] deposition over a very short distance (40–100 μm) [3]. This path length corresponds to a few cell diameters [4]. Typically, alpha particles have LET with a typical energy deposition of 50–100 keV/μm [3]. In comparison, beta-emitting radionuclides release an electron with lower LET (0.2 keV/μm) over a relatively long path length. The differences in the properties between alpha and beta decay are outlined in Table 1.

Table 1.

Key properties of alpha and beta decay, amended from [2]

Type of radiation	Particle	Emission energy per decay (keV)	Path length (μm)	LET (keV/μm)
Alpha (α)	2 protons and 2 neutrons	5,000–9,000	40–100	80
Beta minus (β−)	Electron	50–2300	50–12,000	0.2

The properties of the alpha-emitting radionuclides are well suited to treating metastatic tumours, as the majority of the dose is deposited at the target site, which minimises the toxicity to surrounding healthy tissue [4]. The primary target of high-LET radiation is DNA, and a single alpha particle can result in irreparable double-strand breakage [5], which means fewer particle emissions are required to kill a cell (as compared to β− decay) [3,6]. The double-strand DNA break occurs independent of the cell cycle phase or tissue oxygenation [4] and typically leads to death of a cell and lack of disease recurrence due to the difficulty of repairing a double-strand break. For these reasons, TAT could potentially replace PSMA-targeted Radioligand Therapy (PRLT) with beta-emitting radionuclides or treatment with chemotherapeutic drugs [4]. This is a selective advantage of TAT as a form of oncology treatment.

The alpha-emitting radionuclide itself does not need to be administered during the treatment. Alternatively, a progenitor that will decay to produce the alpha-emitting radionuclide of interest could be used as part of the radiopharmaceutical’s delivery. In these cases, the administered radionuclide should be part of a decay chain which contains an alpha-emitting radionuclide. Using a progenitor (in the form of either a ‘nano-generator’ or ‘local generator’) may be beneficial, as the progenitor’s radioactive properties may be more suited to handling within a research and clinical environment. For example, ²²⁵Ac is an alpha-emitting radionuclide with three other short-lived alpha-emitting radionuclides within its major decay chain (Fig. 1, adapted from [7]). ²²⁵Ac’s progenitor, ²²⁵Ra, decays by emitting a beta particle, yet it can be used as described above to ease the radiopharmaceutical’s production.

Fig. 1.

²²⁵Ra major decay chain, branching under 1% has not been shown.

In practical terms, this criterion can be applied to nuclides by considering only those that are statistically > 10% likely to decay via the emission of an alpha particle. This threshold alpha decay intensity of 10% has been set, as below this limit, the number of alpha particles being released by the nuclide is proportionally outweighed by the other decay route. A low alpha decay intensity is less advantageous as the benefits of using the alpha decay as a treatment option, as discussed above, are not fully exploited. In practice, the criterion for the minimum alpha decay intensity may be set at higher than 10%; however, by setting a low value, a more inclusive list of appropriate radionuclides can be obtained.

• (2)The radionuclide and associated total decay chain (and branches) should have a short radioactive half-life(s), and end in a stable or extremely long-lived radionuclide.

When a nuclide undergoes decay, it does so to release excess energy; the decay product(s) are more stable but may also be radioactive. The decay product(s) will continue to decay in sequential series till a stable nuclide has been reached. The radionuclide and its associated decay chain should have a short half-life to prevent excess dose to the patient. In order for a radionuclide to provide an efficient dose, it should be decaying within very close proximity of the target site. The half-life of the radionuclide should be suited to permit the majority of the radionuclide to decays once the radionuclide has reached the ideal location. Additionally, when the radioactive half-life is too long, patients need to be admitted and isolated for a longer period, hence increasing the treatment cost. The decay chain of the radionuclide should also end in a stable or extremely long-lived radionuclide (such as ²⁰⁹Bi; Fig. 1), to prevent the patient from receiving a long-term radiation dose and hence reduce the time required for the isolation period.

The amount of time that a radionuclide and its progeny remains in the body can depend on (1) the radiopharmaceutical’s biological half-life (defined as the amount of time for the radiopharmaceutical’s concentration in the body to reduce by a half), (2) the radioactive half-life of the radionuclide and its progeny, or (3) the biological half-life of the unchelated radionuclide and its progeny.

When an alpha-emitting radionuclide decays its daughter will becomes separated from the radiopharmaceutical [8]. This decoupling occurs because the recoil energy from the alpha decay is sufficient to break the bonds between the radionuclide and the chelator. This is a direct result of conservation of momentum [9]. The energy distribution between the alpha particle and the recoiling progeny atom is typically 98 to 2% respectively [2] but, even so, the recoil energy of the recoiling daughters is more than 1000 times higher than the binding energy of any chemical bond [10], which leads to the breaking of the chemical bonds between the daughter atom and the targeting vector [2,8]. As a consequence of this decoupling, the daughter has no targeting component, and if it has a long enough half-life this gives time for it to migrate around the body, which can lead to undesirable toxicities as the progeny will have a different bio-distribution from its progenitor [10], as well as off-target accumulation, causing harm to healthy tissue and decreasing the therapeutic dose delivered to the disease site [9,10]. Redistribution of the alpha-emitting radionuclide’s progeny is difficult to quantify; it is influenced by the radionuclide’s half-life and the progeny’s recoil path length, along with biological considerations such as diffusion processes, active transport, and the affinity of the radionuclide for specific organs. These factors impact the toxicity of the radionuclide(s) to specific organs [5] and can therefore limit the radiopharmaceutical’s usefulness. To reduce unwanted irradiation of healthy tissue, the radiopharmaceutical should have a quick uptake at the target site and the quick renal excretion of the unbound alpha-emitting radionuclide (and progeny, due to the recoil effect). Alternatively, a more targeting mechanism of delivery could be used, such as administering the radiopharmaceutical using intra-tumoral injections [4].

In the case where the radionuclide becomes separated from the targeting moiety the effective half-life of the radionuclide is determined by the radioactive half-life and biological half-life within the patient’s body or organs (as described by 2 and 3 above) [11].

The radioactive half-life of radionuclides appropriate for TAT have been well studied, and extensive nuclear data libraries exists. However, the biological half-life of a radiopharmaceutical relies on both the distribution of the alpha-emitting radionuclide and the progeny within the body, which is dependent on the mechanism of delivery [2].

It should also be noted that as the half-life of a nuclide increases, the radioactive specific activity decreases, as displayed in the following equation:

However, alpha decay is commonly considered monoenergetic, as large differences in half-life result in comparatively small differences in alpha particle energy. Therefore, there is not a preference in relation to the energy that the alpha particle is emitted from a TAT radionuclide, but only its half-life.

Since the critical quantity is the alpha dose delivered, a nuclide with a long half-life would require a large mass of the radionuclide, potentially even gram quantities, with obvious chemical toxicity concerns. For example, Table 2 shows the masses of ²¹²Bi and ²²⁵Ac corresponding to a 1MBq activity. By contrast, a nuclide with a very long half-life, such as ¹⁹⁰Pt, would require macroscopic masses that are unsafe to inject into patients in order to provide the same therapeutic radiation dose as the nuclides with shorter half-lives. Indeed, the mass required would be so large that the dose to tissues would be diluted by the agent itself. Finally, the manufacture or separation of such large masses of an isotope would be uneconomic.

Table 2.

Mass equivalence for a 1MBq dose of ²¹²Bi, ²²⁵Ac, and ¹⁹⁰Pt

	Radionuclide of interest
	212Bi	225Ac	190Pt
Half-life	1.09 hours	10 days	6.5 × 1011 years
Mass of 1 MBq (g)	1.65 × 10-12	4.66 × 10-10	9.33 × 103

In order to only consider those radionuclides that can be useful for TAT in microscopic quantities, and those that will not permit the patient to be exposed to radioactivity for a long period of time, this paper has set the specified criterion that the radionuclide should have a half-life of less than 30 days.

• (3)The radionuclide should have a half-life long enough to allow for patient administration.

The half-life of the radionuclide should be long enough to allow for production, radiopharmaceutical synthesis, delivery to the patient, and to be compatible with the pharmacokinetics of tumour localisation [12]. The half-life should be long enough so that the patient receives a radioactive dose large enough to cause a therapeutic effect.

Alternatively, a progenitor with a desirable half-life can be used in conjunction with a shorter-lived alpha-emitting daughter to achieve the same effect via a ‘local generator’ [13] or ‘nano-generator’. A ‘local generator’ is when a radionuclide further up the decay chain with a longer half-life than the TAT nuclide, is supplied in a form that can be ‘milked’ in the laboratory for the grown-in TAT nuclide. A ‘nano-generator’ is a longer-lived nuclide in the chain that decays to the shorter-lived TAT nuclide ‘in situ’ and can hence be used in the drug construct to deliver the progenitor atom to the target, where it decays through the progeny, for example, ²¹²Pb into ²¹²Bi.

In order to only consider radionuclides that have a half-life long enough to permit recovery, purification, conjugation, administration to a patient and in-vivo transport to a target site within the patient, the nuclide (or progenitor) must have a half-life greater than 45 min.

• (4)The radionuclide and its associated decay chain should be able to be handled within a research and clinical environment.

The handling requirements for research and application of a radionuclide must be considered. Though used historically in encapsulated devices, the application of alpha-emitting radon for TAT for instance, would be impractical, due to its gaseous form and lack of chemical reactivity. Radon is a colourless radioactive noble gas, which owing to its stable closed-shell electronic configuration is chemically inert [14].

In practical terms, this criterion can be applied to selecting appropriate TAT nuclides by eliminating the use of radon as a suitable TAT radionuclide, unless its progenitor is used for delivery.

Additionally, radionuclides that decay via spontaneous fission should also be disregarded as a suitable TAT radionuclide. Spontaneous fission results in the release of two daughter radionuclides and several neutrons, the masses of the fragments resulting from fission are not predictable and, therefore, will be challenging to monitor in treatment. The release of neutrons is able to induce radioactivity in tissues and can cause widespread damage to healthy cells, hence such isotopes are not recommended for clinical applications.

Methodology

The IAEA has an interactive library covering the ‘Live Chart of Nuclides’ [15]. The library comprises of evaluated data covering 3359 nuclides, including their decay data. These known nuclides can be presented in a chart of the nuclides [16], where each nuclide is represented by a small square and with the x-axis representing atomic number (number of protons) and the y-axis the number of neutrons in any given nucleus. Thus, nuclides in the same row are isotopes of the same element and nuclides in the same column are nuclides of different elements with the same number of neutrons (isotones). The following trends can be noted:

1. For the proton-rich isotopes of elements up to about lead, the primary decay typically occurs via electron capture or positron emission; this group is represented in Fig. 2 by the blue and orange area to the left of the black ‘valley of stability’ (stable nuclides).

2. For the neutron-rich isotopes of elements up to around lead, the primary decay mode is negative beta decay; represented by the pink region of Fig. 2 to the right of the stable nuclides.

3. As atomic number increases above that of lead, almost no nuclei are stable, electron capture and positron emission become less prominent and alpha decay (yellow areas) becomes the common decay mode, especially for the neutron-rich isotopes of an element. For the heaviest elements, spontaneous fission becomes the primary decay mode for some radionuclides (green boxes).

4. In general, the more distant an isotope of an element is from its more stable isotopes, the shorter its half-lives will be.

Fig. 2.

Chart of the nuclides showing the primary decay mode of each radioactive nuclide [16].

In the IAEA’s Live Chart of the Nuclides [15], the database of 3359 nuclides can be used to select nuclides for direct use, or radionuclides available through use of an immediate progenitor. The nuclear decay criteria to select nuclides for direct use, or available through use of an immediate progenitor, will differ.

There is a balance between the radionuclide’s half-life being sufficiently long to permit recovery, purification, conjugation, administration to a patient and in-vivo transport to a target site within the patient, but not long enough that the patient remains radioactive for a lengthy period or, if the biological half-life of the radionuclide is short, that the patient excretes long-lived radioactivity. Therefore, to identify radionuclides appropriate for TAT the half-life of the alpha emitter itself or that of its progenitor should be within a ‘goldilocks’ region of not being too short, but equally not being too long. In this paper, this requirement has been captured by setting the criteria for radionuclide down-selection as:

1. The nuclide (or progenitor) must have a half-life greater than 45 min

2. The nuclide (or progenitor) must have a half-life less than 30 days

In this methodology, to consider the radionuclides available through use of a progenitor, only the dominant decay route (termed ‘decay_1’ in IAEA’s Live Chart of Nuclides) was used to create a list of daughters produced via alpha, beta-, beta+, and electron capture decay.

The nuclear decay criteria applied to select radionuclides which could be considered for direct use in TAT were (Fig. 3):

Fig. 3.

The nuclide must have a half-life less than 30 days. Down selection of radionuclides to be considered for TAT, without the use of a progenitor. Rn, radon.

1. The nuclide must decay via emission of an alpha particle

2. The nuclide must have a half-life greater than 45 min

3. The nuclide must have a half-life of less than 30 days

4. Alpha decay intensity should be >10% for the decay in question

5. The nuclide does not decay (0%) via spontaneous fission

6. The nuclide should not be Rn (due to handling restrictions).

The radiochemistry criteria applied to down select radionuclides which could be considered for use in TAT, by utilising a progenitor were (Fig. 4):

Fig. 4.

Down selection of radionuclides could be considered for TAT, with the use of a progenitor. Rn, radon.

1. The progenitor should decay via alpha, beta-, beta+, or electron capture

2. The progenitor must have a half-life of less than 30 days

3. The progenitor must have a half-life greater than 45 min

4. The daughter nuclide must decay via emission of an alpha particle

5. The daughter must have a half-life of less than 30 days

6. The daughter’s alpha decay intensity should be >10%

7. The progenitor and daughter nuclides do not decay (0%) via spontaneous fission

8. The progenitor nuclide should not be Rn (due to handling restrictions)

It should be noted, that although the above criteria have been used restrictively in this paper, the criteria themselves should be used as guidelines. It is possible that a radionuclide appropriate for TAT may fall outside of these criteria and that should not be an absolute exclusion. However, to build a picture of where it is best to focus the attention of researchers the criteria have been applied.

Results

Table 3 summarises the nuclides identified using the methodology detailed above as suitable for TAT.

Table 3.

The most applicable nuclides (and their progenitors) appropriate for use in TAT, with their half-lives referenced from [7]

	Progenitor	Primary decay mechanism	Half-life (Hours) [7]	Alpha emitting radionuclide	% of alpha decaya [7]	Half-life (hours) [7]
Appropriate for TAT; through use of a progenitor	212Pb	β−	10.62	212Bi	35.94	1.01
	212Bi	β−	1.01	212Po	100	8.18E-11
	213Bi	β−	0.76	213Po	100	1.03E-09
	211At	EC	7.21	211Po	100	1.43E-04
	223Ra	α	274.32	219Rn	100	1.10E-03
	224Ra	α	87.17	220Rn	100	1.54E-02
	225Ra	β−	357.60	225Ac	100	238.08
	224Ac	EC	2.78	224Ra	100	87.17
	225Ac	α	238.08	221Fr	100	0.08
	226Ac	β−	29.37	226Th	100	0.51
	227Th	α	448.73	223Ra	100	274.32
	230U	α	485.52	226Th	100	0.51
Appropriate for TAT; directly				149Tb	16.7	4.12
				212Bi	35.94	1.01
				211At	41.8	7.21
				223Ra	100	274.32
				224Ra	100	87.17
				225Ac	100	238.08
				227Th	100	448.73
				229U	20	0.97
				230U	100	485.52
				253Fm	12	72.00

^aThe % of alpha decay relates to the intensity % of alpha decay from the decay of the alpha-emitting radionuclide, not the entire decay chain.

In the cases where a chain of nuclides has been identified as appropriate for TAT (e.g. ²²⁵Ra/²²⁵Ac/²²¹Fr), selection of the nuclide higher in the decay chain could result in a higher quantity of alpha particles being released as part of the treatment. This is because the progeny is also able to decay via the release of an alpha particle (effectively constituting a series of nanogenerators); if the progeny were to remain at the target site, it would be able to increase the therapeutic dose.

Discussion

The nuclides and their associated decay chains which this paper has identified as the most applicable for TAT are ¹⁴⁹Tb, ²¹¹At/²¹¹Po, ²¹²Pb/²¹²Bi/²¹²Po, ²¹³Bi/²¹³Po, ²²⁴Ra, ²²⁵Ra/²²⁵Ac/²²¹Fr, ²²⁶Ac/²²⁶Th,²²⁷Th/²²³Ra/²¹⁹Rn, ²²⁹U, ²³⁰U/²²⁶Th, and ²⁵³Fm. As discussed above, the nuclides identified should only be treated as an indicative list of nuclides (and their progenitors) which have the radioactive decay properties most aligned to that for use in TAT.

On comparing the nuclides identified to those already highlighted in the literature, the majority have already been considered for TAT (Fig. 5), which provides confidence in our methodology, although ²²⁹U and ²⁵³Fm are identified here and, based on the criteria developed here, could become new radionuclides of interest for TAT. ²⁵⁵Fm is also identified in the literature as a nuclide of use for TAT [1], but is excluded here due to its spontaneous fission decay.

Fig. 5.

Nuclides appropriate for TAT previously identified within literature

The criterion of having a half-life less than 30 days is arbitrary but, on increasing this value to 50 days, no additional radionuclides are identified. ²⁵⁸Md is the next radionuclide that would meet the nuclear decay criteria, with a half-life of 51.5 days.

A number of constraints were applied during the methodology, for example, the down-selection study did not consider the consequence of toxic species being present within the radionuclide’s decay chain. For example, both ²³⁰U and ²²⁶Ac have ²¹⁰Po within their decay chains, a radionuclide with high specific activity and deadly associations. The relative activities and impact of the long-term presence of possible toxic species, such as ²¹⁰Po, in the body are presently being evaluated. Additionally, consideration on the physical properties has been limited to the progenitors and nuclides of interest, not the complete decay chain, for example, the ²⁵³Fm decay chain has a small but present spontaneous fission decay with the presence of ²⁴¹Am, ²⁴⁹Bk, ²⁴⁹Cf and ²⁵³Es within its decay chain. The implications of the presence of such radionuclides in the decay chain are also currently being evaluated.

Conclusion

TAT is a promising form of oncology treatment, but its development has been inhibited by the lack of appropriate radionuclides. Candidate radionuclides can be identified based on nuclear decay properties which are the only immutable requirement. Other factors such as biochemistry and economic factors can be changed, whereas the nuclear decay properties are fixed to that nuclide. Therefore, the selection of a radionuclide suitable for TAT should be weighted by its nuclear decay properties, which predominantly means meeting the criterion of being (or generating) an alpha emitter with a suitable half-life.

From an overarching nuclear emissions criterion, a down-selection exercise has been completed, and shown that the most appropriate radionuclides, based on nuclear decay properties, are: ¹⁴⁹Tb, ²¹¹At/²¹¹Po, ²¹²Pb/²¹²Bi/²¹²Po, ²¹³Bi/²¹³Po, ²²⁴Ra, ²²⁵Ra/²²⁵Ac/²²¹Fr, ²²⁶Ac/²²⁶Th,²²⁷Th/²²³Ra/²¹⁹Rn, ²²⁹U, ²³⁰U/²²⁶Th, and ²⁵³Fm, the majority of which have already been considered for TAT, which suggests the criteria give consistent results. By the criteria developed here, ²²⁹U and ²⁵³Fm are also identified as new radionuclides of interest for TAT, depending on their decay chain progeny.

Further work investigating these radionuclides to consider the implications of the progeny in each decay chain is underway and will be published at a later date.

Acknowledgements

S. Ree acknowledges financial support through the industrial fellowship scheme of the Royal Commission for the Exhibition of 1851, UK. The authors would also like to acknowledge the support of the NNL Health and Nuclear Medicine Signature Research Programme.

Conflicts of interest

There are no conflicts of interest.