Availability of Alpha-Emitting Radioisotopes by Reactor and Accelerator Production and via Decay of Naturally Occurring Parents

and Ashutosh Dash²

(1)

Nuclear Security and Isotope Division, Oak Ridge National Laboratory, OAK RIDGE, USA

(2)

Isotope Production and Applications Division, Bhabha Atomic Research Centre, Mumbai, India

8.1 Introduction

Because of the very high LET and opportunity to sterilize target cells without the potential irradiation and damage of nontarget adjacent cells which is encountered with the use of beta-emitting radioisotopes, interest in the use of alpha emitters, especially for oncology applications, has dramatically increased in the last decade. Very eloquent chemistry and innovation production strategies have provided access to adequate activity levels of many of these desired radioisotopes for the first time. Table 8.1 provides properties of representative radionuclides in various decay chains which provide alpha-emitting radioisotopes of interest for targeted alpha therapy (TAT) key information for key alpha-emitting radioisotopes of current and expected interest. Chapter 2 introduces and provides key examples of the biological strategies for targeting alpha emitters, and Chaps. 6 and 7 provide introduction to the use of both research reactors and accelerators for production of these species, and Chap. 7 discusses radionuclide generator systems which provide several alpha emitters of interest. This chapter is dedicated to a discussion of the processing and purification chemistry which are required to obtain these radioisotopes for subsequent radiolabeling and biological investigation.

Table 8.1

Radioactive properties of representative radionuclides in decay chains which provide alpha-emitting radioisotopes of interest for targeted alpha therapy (TAT)^a

Radioisotope	Half-life	Decay mode	Radiation energy			Comment
Radioisotope	Half-life	Decay mode	Alpha MeV	Beta MeV	Gamma keV	Comment
Actinium radioisotopes
Actinium-225	10 days	α	5.935 (100 %)		99.8	Parent of ²¹³Bi
Actinium-227	21.77 years	α	5.042 (1.38 %)	0.0449 (98.6 %)	100	Parent of ²²⁷Th/²²³Ra
Bismuth radioisotopes
Bismuth-212	61 m	α, β⁻	6.207 (35.9 %)	2.254 (64 %)	238, etc.
Bismuth-213	45 m	α, β⁻	5.982 (2.09 %)	1.427 (97.91 %)	440
Lead radioisotopes
Lead-212	10.6 h	β⁻		0.574 (100 %)	0.15	Parent of ²¹²Bi
Radium radioisotopes
Radium-223	11.43 days	α	5.979 (100 %)		269, etc.	²²³RaCl₂ = Xofigo®
Radium-224	3.66 days	α	5.788 (100 %)		240, etc.	Parent of ²¹²P
Radium-226	1,600 years	α	4.870 (100 %)		186	Important target material
Thorium radioisotopes
Thorium-227	18.65 days	α	6.146 (100 %)		236, etc.	Parent of ²²³Ra
Thorium-228	1.912 years	α	5.520 (100 %)		216, etc.	Parent of ²²⁴Ra
Thorium-229	7.34 × 10³ years	α	5.187 (100 %)		193, etc.	Parent of ²²⁵Ac
Thorium-232	1.405 × 10¹⁰ years	α	4.082 (100 %)		59	Parent of ²²⁸Th, ²²⁴Ra

^aData from Firestone and Ekstrom (2004)

8.2 Production and Processing of Alpha Emitters in the Thorium Series

8.2.1 Actinium-225

Actinium-225 (T _1/2 = 10.0 days) can be obtained from decay of ²²⁹Th (Fig. 8.1) and decays by emission of three alpha-particles through the ²²¹Fr (half-life, 4.8 min)/²¹⁷ at (half-life, 32.3 ms)/²¹³Bi (half-life, 45.6 min) decay chain. There are several avenues to obtain ²⁹⁹Th which include neutron irradiation of ²³²Th which leads to ²³³U, from which α-decay forms ²²⁹Th, with subsequent α-decay to ²²⁵Ac. Another strategy is reactor irradiation of ²²⁶Ra, by multiple neutron captures and also provides ^229Th (see Chap. 3). Because of its very long 7340-year half-life, ²²⁹Th represents a convenient source material to obtain ²²⁵Ac on a regular basis by elution of the ²²⁹Th/²²⁵Ac generator. In addition, ²²⁵Ac has been directly produced via 800 MeV high-energy irradiation of natural thorium (²³²Th) targets (Zhuikov et al. 2012). Actinium-225 is being evaluated for in vivo therapeutic applications because of its useful half-life of 10 days and emission of multiple α-particles. In addition, the ²²⁵Ac/²¹³Bi generator provides the short-lived (half-life 45 m in) ²¹³Bi alpha emitter which has been widely studied for targeted alpha therapy (see Chap. 3).

Fig. 8.1

The ²²⁵Ac and ²¹³Bi decay chain. The ²²⁵Ac is obtained as the decay product of ²²⁹Th and decays by α-emission through ²²¹Fr, ²¹⁷At, and ²¹³Bi, each of which also emits an α-particle

There are several production strategies to provide ²²⁵Ac from ²²⁶Ra which include irradiation in a nuclear reactor where there is successive multiple neutron capture on ²²⁶Ra. A mixture of ²²⁷Ac, ²²⁸Th, and ²²⁹Th is produced (Boll et al. 1997), from which ²²⁹Th can be directly obtained with a relatively high yield and ²²⁵Ac can be isolated by ion exchange separation method using titanium phosphate adsorbent. Another promising production pathway is via the ²²⁶Ra(p,2n)²²⁵Ac proton-induced reaction using 18 MeV protons which requires repeated irradiation of ²²⁶Ra. After production, ²²⁵Ac requires purification on a Dowex-50 column (Geerlings et al. 1993) before use for radiolabeling or for fabrication of the ²²⁵Ac/²¹³Bi generator. A more recent strategy involves the 200 MeV high-energy spallation of natural thorium targets (²³²Th) (Weidner et al. 2012). The preliminary cross section data have suggested that multi-Curie activity levels of both ²²⁵Ac and ²²³Ra can be produced using accelerators available at both BNL and LANL. Other routes which have been proposed but evidently not yet evaluated include the use of alpha-particles for ²²⁹Th production by the ²²⁶Ra(³He,γ)²²⁹Th and ²²⁶Ra(α,n)²²⁹Th reactions (Mirzadeh and Garland 2010).

Production of ²²⁷Ac is also possible by the ²²⁶Ra + γ → ²²⁵Ra + n photonuclear reaction. This reaction is virtually instantaneous, so that ²²⁵Ra activity levels reach a maximum value after irradiation and will decrease slowly over time (Melville et al. 2006). Since there is no direct production avenue to provide ²²⁵Ac from the irradiation of ²²⁶Ra, the natural decay of ²²⁵Ra is utilized where ²²⁵Ra subsequently decays to ²²⁵Ac by beta emission (T _1/2 = 14.8 days) by the ²²⁵Ra $\overset{\beta^{-}}{\to }$ ²²⁵Ac decay reaction.

The therapeutic use of the actinium alpha emitters provides greater cytotoxicity than use of ²¹³Bi-labeled agents since the ²²⁵Ac 10.0 days half-life and emission of 4 alpha-particles from decay of ²²⁷Ac, as demonstrated in the prolonged survival of mouse xenograft models for several types of experimental cancers (McDevitt et al. 2001). A major expected impediment of using ²²⁵Ac for many therapeutic strategies is that the chelation binding energy is not strong enough to withstand the recoil energy released during alpha-particle emission of the actinium ion (between 100 and 200 keV). This energy usually release the ²²⁵Ac from chelate stabilization sphere (Davis et al. 1999; Kennel and Mirzadeh 1998; Deal et al. 1999). In this manner, the ²²⁵Ac daughter radionuclides are released from the localized site selectivity and diffuse away, causing cell damage in normal tissue (McDevitt et al. 1998; Schwartz et al. 2011). However, methods for stabilization of the ²²⁵Ac to recoil release of decay products have been evaluated, and simple gold-coated nanoparticles have exhibited stability in animal studies (McLaughlin et al. 2013).

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